NM_000251.3:c.1619G>C (p.Ser540Thr) is a missense variant in MSH2 exon 10. It is extremely rare in population databases (gnomAD v4.1 AF = 8.67e-06, 14/1,613,934 alleles), meeting PM2_Supporting under the InSiGHT MSH2 VCEP v2.0.0 threshold of <0.00002.1 Multiple lines of computational evidence (HCI prior = 0.0006, SpliceAI max delta = 0.03, REVEL = 0.276, BayesDel = -0.242779) predict a neutral effect, meeting BP4_Supporting under the InSiGHT MSH2 VCEP v2.0.0 threshold of HCI prior < 0.11.2 Functional data from a calibrated massively parallel assay (PMID:33357406) exists for MSH2 missense variants but the variant-specific LoF score for p.Ser540T could not be verified from the available full text; PS3/BS3 remain not assessed pending supplementary data review.3 ClinVar reports this variant as Uncertain Significance (3 clinical laboratories) and Benign (1 clinical laboratory), with no expert panel review. PP5 is not applicable under this VCEP.4 This variant has been observed in COSMIC (n=1 somatic occurrence) but does not lie in a statistically significant mutational hotspot.
MSH2
Final classification
Uncertain Significance - Conflicting Evidence
MSH2 c.1619G>C · p.Ser540Thr
MSH2
NM_000251.3:c.1619G>C (p.Ser540Thr) is a missense variant in MSH2 exon 10. It is extremely rare in population databases (gnomAD v4.1 AF = 8.67e-06, 14/1,613,934 alleles), meeting PM2_Supporting under the InSiGHT MSH2 VCEP v2.0.0 threshold of <0.00002.
Richards et.al., 2015 - Combining rules v2.0.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP4 supporting benign; maps to Uncertain Significance - Conflicting Evidence.
Classification rationale
PM2
BP4
Uncertain Significance - Conflicting Evidence
MSH2 c.1619G>C
PM2 + BP4
→
Uncertain Significance - Conflicting Evidence
Gene diagram
· NM_000251.3 · variants mapped to exon structure
MSH2
NM_000251.3
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 8.67446e-06; MAF= 0.00087%, 14/1613934 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.20031e-05; MAF= 0.00320%, 2/62494 alleles, homozygotes = 0); grpmax FAF= 5.42e-06.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00087%
· 14 / 1,613,934
0 hom · FAF 0.00054%
0 hom · FAF 0.00054%
Remaining individuals 2 / 62,494 |
0.0032% |
European (non-Finnish) 12 / 1,179,880 |
0.001% |
+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 487021)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.276. BayesDel score = -0.242779. HCI prior probability for pathogenicity = 0.0006. MAPP score = 2.19. Custom PP2 score = 0.003.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MSH2, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial cancers.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV105858650, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 7 PMIDs not cited in assessment
25070057 ↗
Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
33357406 ↗
Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk.
CLINVAR
22167527 ↗
Identification of individuals at risk for Lynch syndrome using targeted evaluations and genetic testing: National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Colorectal Cancer joint practice guideline.
CLINVAR
23408351 ↗
Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts.
CLINVAR
23788249 ↗
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
CLINVAR