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Gene-disease assertions not curated here (add link or write note):

Disease

Lynch syndrome

Inheritance

Autosomal autosomal dominant

Prevalence

 1:279

Source: PMID: 20301390

Rapid or full curation?

  • Rapid
  • Full

ClinGen / GenCC / BabySeq / HGMD

Hereditary Cancer GCEP, accessed 07.21.2023

Clinical Validity Scoring Notes and points

Lynch syndrome [MONDO:0005835], also known as Hereditary Nonpolyposis Colon Cancer [MONDO:0018630], is a group of autosomal dominant cancer predisposing syndrome. It is characterized by a familial predisposition to early-onset colorectal carcinoma (CRC) and extra- colonic tumors of the gastrointestinal, urological and female reproductive tracts. MSH2 has been linked to Lynch Syndrome, or HNPCC in the early 1990s (PMID: 8261515 and 8252616). Of note, this gene has also been implicated in autosomal recessive mismatch repair cancer syndrome 1 (MONDO:0010159), which has been assessed separately. MSH2 gene encodes MSH2 protein, which heterodimerizes with MSH6 or MSH3 to form MSH2-MSH6 or MSH2-MSH3 complex (also named MutSα and MutSβ, respectively). Both MutSα and MutSβ are required for the DNA mismatch repair (MMR) pathway. Defective MMR pathway is responsible for microsatellite instability, a type of genomic instability that is characteristic for tumor cells. Loss of function variants in MSH2 gene have been repetitively reported in families and individuals from various populations. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Eight loss of function variants in this gene reported in 9 probands from 9 families in 2 publications (PMID:18566915, 32161499) is included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease association is also supported by expression, functional studies (6 points) demonstrating MSH2’s role in mismatch repair and mouse models (PMIDs: 19324997, 7550317, 7628020). Homozygous Msh2-/- mice began, with high frequency, to develop lymphoid tumors containing microsatellite instabilities at an early age. In addition, Msh2-deficient mouse ES cells lost mismatch binding and acquired microsatellite instability. In summary, MSH2 is definitively associated with autosomal dominant Lynch syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Source: Hereditary Cancer GCEP, accessed 07.21.2023

Clinical Validity Points Total

18

Source: Hereditary Cancer GCEP, accessed 07.21.2023

Clinical Validity Classification

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Definitive

Source: Hereditary Cancer GCEP, accessed 07.21.2023

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function

Source: Hereditary Cancer GCEP, accessed 07.21.2023. PMID: 18566915, 32161499.

Penetrance

 options

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Moderate

Source: PMID: 20301390

Age of Onset

 options

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Adulthood

Severity

 Options

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

Moderate

Clinical Features

Increased risk of cancers, including colorectal, endometrial, ovarian, stomach/small bowel, ureter/kidney, bladder, prostate, brain, breast

Source: PMID: 20301390

HPO Terms

https://hpo.jax.org/app/

HP:0003003 Colon cancer

HP:0006725 Pancreatic adenocarcinoma

HP:0200008 Intestinal polyposis

HP:0012114 Endometrial carcinoma

HP:0012125 Prostate cancer

HP:0002862 Bladder carcinoma

Gene SOPs & Notes

Curation Summary

 Examples

- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dsiease relationship is limited

Case ID, Curator name, Date, Jira ticket link

Disease

Lynch sy

Inheritance

Autosomal recessive / autosomal dominant / X-linked

Prevalence

 

Source:

Rapid or full curation?

  • Rapid
  • Full

ClinGen / GenCC / BabySeq / HGMD

Clinical Validity Scoring Notes and points

Variant/Case Evidence:

Segregation Evidence:

Case/Control Evidence:

Experimental Evidence:

Source:

Clinical Validity Points Total

Source:

Clinical Validity Classification

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Source:

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function / Gain of function / Dominant Negative

Penetrance

 options

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

 options

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

 Options

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

Clinical Features

Sources:

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

 Examples

- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dsiease relationship is limited

Case ID, Curator name, Date, Jira ticket link

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