rs63749889
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000179.3(MSH6):c.2702G>A(p.Arg901His) 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 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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. R901C) 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_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.2702G>A | p.Arg901His | missense_variant | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.2702G>A | p.Arg901His | missense_variant | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152152Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250638Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135538
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461862Hom.: 0 Cov.: 34 AF XY: 0.00000825 AC XY: 6AN XY: 727232
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74336
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 24, 2022 | The p.R901H variant (also known as c.2702G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 2702. The arginine at codon 901 is replaced by histidine, an amino acid with highly similar properties. This alteration was detected in conjunction with a protein-truncating MLH1 mutation in a proband diagnosed with both endometrial and colon cancer whose mother had early-onset colon cancer (Charames GS et al. Hum Genet. 2000 Dec;107(6):623-9). 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 05, 2022 | This missense variant replaces arginine with histidine at codon 901 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 affected with pancreatic cancer (PMID: 32980694). This variant was also reported in an individual affected with colorectal and endometrial cancer, however, they also carried a pathogenic MLH1 variant (reported as 397delT, fs400stop; PMID: 11153917) that could explain the observed phenotype. This variant has been identified in 7/282034 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in the 4/13855 Chinese population samples (PMID: 34172528). 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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 10, 2023 | This missense variant replaces arginine with histidine at codon 901 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 affected with pancreatic cancer (PMID: 32980694). This variant was also reported in an individual affected with colorectal and endometrial cancer, however, they also carried a pathogenic MLH1 variant (reported as 397delT, fs400stop; PMID: 11153917) that could explain the observed phenotype. This variant has been identified in 7/282034 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in the 4/13855 Chinese population samples (PMID: 34172528). 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 | Sep 03, 2019 | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in an individual with a personal history of colon and endometrial cancer who was also found to harbor a MLH1 pathogenic variant (Charames 2000).; This variant is associated with the following publications: (PMID: 23621914, 26333163, 11153917) - |
Endometrial carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 23, 2023 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at