NM_000251.3:c.317G>A
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The NM_000251.3(MSH2):c.317G>A(p.Arg106Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000187 in 1,611,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000790 AC: 12AN: 151964Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251312Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135826
GnomAD4 exome AF: 0.000199 AC: 290AN: 1459846Hom.: 0 Cov.: 31 AF XY: 0.000222 AC XY: 161AN XY: 726338
GnomAD4 genome AF: 0.0000790 AC: 12AN: 151964Hom.: 0 Cov.: 31 AF XY: 0.0000809 AC XY: 6AN XY: 74196
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:4
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Variant summary: MSH2 c.317G>A (p.Arg106Lys) results in a 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 7.1e-05 in 253718 control chromosomes (gnomAD and publication). This frequency is not higher than estimated for a pathogenic variant in MSH2 causing Lynch Syndrome (7.1e-05 vs 0.00057), allowing no conclusion about variant significance. c.317G>A has been reported in a proband from LS family with lack of co-segregation of this variant with disease. This patient also carried a pathogenic variant in MLH1, which could explain the patients phenotype (Spaepen_2006). The variant of interest has also been reported in a case-control study with comparable allele frequency detected in the control and case cohorts (Barnetson_2008). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18033691, 16736289, 22290698, 22949387, 31569399). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
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Lynch syndrome 1 Benign:2
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not provided Benign:2
This variant is associated with the following publications: (PMID: 22949387, 22290698, 18033691, 16736289) -
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Hereditary cancer-predisposing syndrome Benign:2
This alteration is classified as 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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Breast and/or ovarian cancer Benign:1
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Lynch syndrome Benign:1
Multifactorial likelihood analysis posterior probability <0.001 -
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