chr2-47806206-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong
The NM_000179.3(MSH6):āc.3649A>Gā(p.Arg1217Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000316 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_000179.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152214Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461666Hom.: 0 Cov.: 33 AF XY: 0.0000248 AC XY: 18AN XY: 727158
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74356
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 12, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 family with prostate cancer and demonstrated "partial" segregation (not sure what that means, but other uses of this term in the paper included examples of nonsegregation, ie affected individuals who did not carry the variant); ClinVar: 1 VUS - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 27, 2023 | Variant summary: MSH6 c.3649A>G (p.Arg1217Gly) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mut S, C-terminal domain (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251192 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3649A>G has been reported in the literature in individuals affected with prostrate cancer (Leongamornlert_2014), colon cancer of cecum with proficient MMR status (Pearlman_2017), and sebaceous neoplasms with loss of MLH1 and PMS2 on tumor IHC and no significant family history (Schon_2018). These report(s) do not provide unequivocal conclusions about association of the variant with MSH6-associated Lynch syndrome. 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: 24556621, 27978560, 29333623). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 20, 2023 | This missense variant replaces arginine with glycine at codon 1217 of the MSH6 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal adenocarcinoma, sebaceous neoplasms, and prostate cancer (PMID: 24556621, 27978560, 29333623). This variant has been identified in 1/31404 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 | Ambry Genetics | Feb 01, 2023 | The p.R1217G variant (also known as c.3649A>G), located in coding exon 8 of the MSH6 gene, results from an A to G substitution at nucleotide position 3649. The arginine at codon 1217 is replaced by glycine, an amino acid with dissimilar properties. This has been identified in individuals with a personal and/or family history of prostate cancer (Leongamornlert D et al Br J Cancer. 2014 Mar 18;110(6):1663-72; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This alteration has also been previously identified in an individual from a North American cohort of individuals with early onset colon cancer (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 30, 2024 | This missense variant replaces arginine with glycine at codon 1217 of the MSH6 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal adenocarcinoma, sebaceous neoplasms, and prostate cancer in the literature (PMID: 24556621, 27978560, 29333623). This variant has been identified in 1/31404 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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 06, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with sebaceous neoplasm, cecal, or prostate cancer (Leongamornlert et al., 2014; Pearlman et al., 2017; Schon et al., 2018; Matejcic et al., 2020); This variant is associated with the following publications: (PMID: 24556621, 27978560, 29596542, 29333623, 12019211, 17531815, 21120944, 32832836) - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 28, 2024 | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1217 of the MSH6 protein (p.Arg1217Gly). This variant is present in population databases (rs587780677, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal cancer, prostate cancer, and sebaceous neoplasm (PMID: 24556621, 27978560, 29333623). ClinVar contains an entry for this variant (Variation ID: 135842). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Endometrial carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 04, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at