2-47403246-T-C
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP3BP4_ModerateBP6
The NM_000251.3(MSH2):āc.55T>Cā(p.Phe19Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000925 in 1,599,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000571 AC: 87AN: 152264Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000110 AC: 24AN: 219030Hom.: 0 AF XY: 0.0000837 AC XY: 10AN XY: 119524
GnomAD4 exome AF: 0.0000422 AC: 61AN: 1447130Hom.: 0 Cov.: 31 AF XY: 0.0000348 AC XY: 25AN XY: 718710
GnomAD4 genome AF: 0.000571 AC: 87AN: 152382Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37AN XY: 74520
ClinVar
Submissions by phenotype
Lynch syndrome 1 Uncertain:2Benign:2
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. -
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Hereditary cancer-predisposing syndrome Benign:4
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The missense variant NM_000251.3(MSH2):c.55T>C (p.Phe19Leu) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. There is a small physicochemical difference between phenylalanine and leucine, which is not likely to impact secondary protein structure as these residues share similar properties. The p.Phe19Leu missense variant is predicted to be damaging by both SIFT and PolyPhen2. The phenylalanine residue at codon 19 of MSH2 is conserved in all mammalian species. The nucleotide c.55 in MSH2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Benign -
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
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not specified Uncertain:1Benign:2
DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.55T>C, in exon 1 that results in an amino acid change, p.Phe19Leu. This sequence change does not appear to have been previously described in individuals with MSH2-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.20% in the African subpopulation (dbSNP rs141711342). The p.Phe19Leu change affects a highly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Phe19Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Phe19Leu change remains unknown at this time. -
Variant summary: MSH2 c.55T>C (p.Phe19Leu) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain (IPR007695) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 219030 control chromosomes, predominantly at a frequency of 0.0018 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.55T>C has been reported in the literature in individuals affected with Colorectal Cancer (e.g. Thompson_2013) and breast cancer (e.g. Maxwell_2014) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variant(s) have been reported (MLH1 c.1624C>T, p.Gln542X), providing supporting evidence for a benign role. At least one publication reports the variant as non-pathogenic based on a genetic screen that assesses the MMR-abrogating effect of endogenously expressed Msh2 variants in mESCs (example, Houlleberghs_2016). The following publications have been ascertained in the context of this evaluation (PMID: 22949387, 25503501, 26951660, 30998989). ClinVar contains an entry for this variant (Variation ID: 182595). Based on the evidence outlined above, the variant was classified as likely benign. -
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MSH2-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Breast and/or ovarian cancer Benign:1
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Hereditary nonpolyposis colon cancer Benign:1
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not provided Benign:1
This variant is associated with the following publications: (PMID: 25503501, 22949387, 25256751) -
Hereditary nonpolyposis colorectal neoplasms Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at