rs587779113
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_000251.3(MSH2):c.182A>C(p.Gln61Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000311 in 1,606,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q61H) has been classified as Likely benign.
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.182A>C | p.Gln61Pro | missense_variant | 1/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.182A>C | p.Gln61Pro | missense_variant | 1/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000430 AC: 1AN: 232376Hom.: 0 AF XY: 0.00000785 AC XY: 1AN XY: 127426
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1454734Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 722960
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74372
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 19, 2021 | This missense variant replaces glutamine with proline at codon 61 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental studies have reported this variant protein to be functional in yeast mutator and protein binding assays (PMID: 17720936, 20176959). This variant has been reported in an individual affected with ovarian and colorectal cancer (PMID: 25133505). This variant has been identified in 1/232376 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 04, 2020 | 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. - |
Lynch syndrome 1 Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 22, 2023 | This variant is considered likely benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 13, 2017 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 07, 2023 | Variant summary: MSH2 c.182A>C (p.Gln61Pro) results in a non-conservative amino acid change located in the N-terminal domain (IPR007695) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-06 in 232376 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.182A>C has been reported in the literature in an individual affected with ovarian cancer and colorectal cancer who fulfilled at least one of the revised Bethesda guidelines and in affected individuals undergoing genetic testing for hereditary cancers (e.g. Tsaousis_2019, Germani_2020, Pemov_2021). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Functional studies examining the variant in a yeast model system and using a DNA mismatch repair proficiency screen showed no damaging effect of this variant (Gammie_2007, Jia_2021). The following publications have been ascertained in the context of this evaluation (PMID: 17720936, 32957588, 33357406, 25133505, 34964002, 31159747). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=3) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 30, 2023 | This missense variant replaces glutamine with proline at codon 61 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental studies have reported this variant protein to be functional in yeast mutator and protein binding assays (PMID: 17720936, 20176959). This variant has been reported in an individual affected with ovarian and colorectal cancer (PMID: 25133505). This variant has been identified in 1/232376 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 26, 2020 | This variant is associated with the following publications: (PMID: 16995940, 17720936, 26333163, 25133505, 18383312, 20176959, 31159747, 32957588) - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at