2-47800330-T-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_Strong
The NM_000179.3(MSH6):c.2347T>A(p.Cys783Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,072 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. C783Y) has been classified as Uncertain significance.
Frequency
Consequence
NM_000179.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.2347T>A | p.Cys783Ser | missense_variant | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.2347T>A | p.Cys783Ser | missense_variant | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251076Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135674
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461878Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727238
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74346
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 01, 2022 | This missense variant replaces cysteine with serine at codon 783 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 an individual affected with breast cancer (PMID: 35039564). This variant has been identified in 2/282480 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 | Jul 18, 2022 | The p.C783S variant (also known as c.2347T>A), located in coding exon 4 of the MSH6 gene, results from a T to A substitution at nucleotide position 2347. The cysteine at codon 783 is replaced by serine, an amino acid with dissimilar properties. 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 19, 2022 | - - |
Lynch syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 30, 2023 | This missense variant replaces cysteine with serine at codon 783 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/282480 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:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 23, 2023 | In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 35039564 (2022), 35264596 (2022)). The frequency of this variant in the general population, 0.0000071 (2/282480 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 10, 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; Identified in individuals with breast cancer (Eygelaar et al., 2022; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 23621914, 17531815, 21120944, 35039564, 35264596) - |
Lynch syndrome 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Dec 01, 2021 | The MSH6 c.2347T>A (p.Cys783Ser) missense change has a maximum subpopulation frequency of 0.0080% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/variant/2-48027469-T-A?dataset=gnomad_r2_1). Seven of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting, PP3. - |
MSH6-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 28, 2023 | The MSH6 c.2347T>A variant is predicted to result in the amino acid substitution p.Cys783Ser. This variant has been reported in two individuals with breast cancer and classified as a variant of uncertain significance in both studies (Eygelaar et al. 2022. PubMed ID: 35039564; Guindalini et al. 2022. PubMed ID: 35264596). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48027469-T-A). It is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/233180/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Endometrial carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 01, 2024 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at