rs561198849
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3
The NM_000179.3(MSH6):c.2291C>A(p.Thr764Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/20 in silico tools predict a benign 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. T764I) has been classified as Uncertain significance.
Frequency
Consequence
NM_000179.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.2291C>A | p.Thr764Asn | missense_variant | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.2291C>A | p.Thr764Asn | missense_variant | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251148Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135722
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461876Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10AN XY: 727238
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74324
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 05, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 01, 2022 | The p.T764N variant (also known as c.2291C>A), located in coding exon 4 of the MSH6 gene, results from a C to A substitution at nucleotide position 2291. The threonine at codon 764 is replaced by asparagine, an amino acid with similar properties. This variant has been identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome and tumor demonstrated high microsatellite instability; however, this variant was seen in conjunction with a pathogenic MLH1 variant (Casey G et al. JAMA 2005 Feb;293(7):799-809). This variant was also reported in one of 711 Russian women with breast cancer but was absent from 492 healthy controls. The patient with this variant also reportedly carried a BRCA2 pathogenic mutation (Nikitin AG et al. Front Oncol, 2020 May;10:666). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 08, 2022 | This missense variant replaces threonine with asparagine at codon 764 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with colorectal cancer, however, this individual also carried a pathogenic variant in the MLH1 gene that could explain the observed phenotype (PMID: 15713769). This variant has also been reported in an individual affected with hereditary breast cancer (PMID: 32547938). This variant has been identified in 5/282546 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. - |
Lynch syndrome 5 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 29, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 28, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 01, 2020 | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including breast cancer (Nikitin 2020); Observed in an individual in published literature (Casey 2005) who had a different genetic etiology for colorectal cancer; This variant is associated with the following publications: (PMID: 15713769, 23621914, 32547938) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 20, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 10, 2022 | Variant summary: MSH6 c.2291C>A (p.Thr764Asn) results in a non-conservative amino acid change DNA mismatch repair protein MutS core (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251148 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2291C>A has been reported in the literature in individuals affected with Colorectal cancer and Breast cancer without stong evidence for causality (Casey_2005, Nikitin_2020). These data do not allow any conclusion about variant significance. Co-occurrence with another pathogenic variant have been reported (MLH1 c.350C>G, p.Thr117Arg), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. 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 | Aug 15, 2023 | This missense variant replaces threonine with asparagine at codon 764 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with colorectal cancer, however, this individual also carried a pathogenic variant in the MLH1 gene that could explain the observed phenotype (PMID: 15713769). This variant has also been reported in an individual affected with hereditary breast cancer (PMID: 32547938). This variant has been identified in 5/282546 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. - |
Endometrial carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 12, 2023 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at