rs63750753
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 5P and 5B. PM1PM5PP3BP6BS1
The NM_000179.3(MSH6):c.3260C>A(p.Pro1087His) variant causes a missense change. The variant allele was found at a frequency of 0.000116 in 1,614,028 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. P1087A) has been classified as Likely benign.
Frequency
Consequence
NM_000179.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.3260C>A | p.Pro1087His | missense_variant | 5/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.3260C>A | p.Pro1087His | missense_variant | 5/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000986 AC: 15AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000131 AC: 33AN: 251432Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135896
GnomAD4 exome AF: 0.000118 AC: 172AN: 1461884Hom.: 0 Cov.: 33 AF XY: 0.000118 AC XY: 86AN XY: 727240
GnomAD4 genome ? AF: 0.0000986 AC: 15AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74334
ClinVar
Submissions by phenotype
not specified Uncertain:2Benign:1Other:1
Uncertain significance, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 10, 2024 | Variant summary: MSH6 c.3260C>A (p.Pro1087His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) 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 0.00012 in 327960 control chromosomes, predominantly at a frequency of 0.00052 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 3.66 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.3260C>A has been reported in the literature in individuals affected with breast cancer, ovarian cancer, endometrial cancer, biliary tract cancer, and colorectal cancer (example, Lu_2015, Kanchi_2014, Rubio_2016, Patel_2018, Kwong_2020, Ackay_2021, Djursby_2022, Okawa_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. 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: 32658311, 24728327, 35904628, 24448499, 32068069, 26689913, 36243179, 30072391, 27398995, 23621914). ClinVar contains an entry for this variant (Variation ID: 127584). Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 14, 2021 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10537275, 24728327, 23621914, 27398995, 26689913, 17594722, 10508506, 17531815, 22851212, 12019211, 21120944, 22102614, 29596542, 30072391) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 14, 2023 | In the published literature, this variant has been reported in individuals with colorectal cancer (PMIDs: 30072391 (2018), 35904628 (2022)), gastric cancer (PMID: 26689913 (2015)), endometrial cancer (PMID: 27398995 (2016)), and breast cancer (PMIDs: 26689913 (2015), 32068069 (2020), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). The frequency of this variant in the general population, 0.00051 (18/35424 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 02, 2023 | This missense variant replaces proline with histidine at codon 1087 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 endometrial cancer (PMID: 27398995), breast cancer (PMID: 26689913, 32068069, 32658311), gastric cancer (PMID: 26689913), acute myeloid leukemia (PMID: 26689913), or colorectal cancer (PMID: 30072391), as well as in a healthy control individual (PMID: 24728327). This variant has been identified in 35/282836 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 25, 2022 | 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 12, 2022 | - - |
Lynch syndrome 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Jan 17, 2020 | - - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces proline with histidine at codon 1087 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 endometrial cancer (PMID: 27398995), breast cancer (PMID: 26689913, 32068069, 32658311), gastric cancer (PMID: 26689913), acute myeloid leukemia (PMID: 26689913), or colorectal cancer (PMID: 30072391), as well as in a healthy control individual (PMID: 24728327). This variant has been identified in 35/282836 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. - |
MSH6-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 14, 2023 | The MSH6 c.3260C>A variant is predicted to result in the amino acid substitution p.Pro1087His. This variant has been reported in individuals with endometrial cancer (Rubio et al. 2016. PubMed ID: 27398995) breast cancer (Kwong et al. 2020. PubMed ID: 32068069) colon cancer (Patel et al. 2018. PubMed ID: 30072391) and various other cancer types (Lu et al. 2015. PubMed ID: 26689913). However, this variant was also reported in individuals from a healthy control cohort (Bodian et al. 2014. PubMed ID: 24728327). This variant is reported in 0.051% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48030646-C-A). In ClinVar, this variant has conflicting interpretations of pathogenicity, from likely benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127584/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Mismatch repair cancer syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 09, 2021 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at