rs786203670
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM2PM5BP4_ModerateBP6
The NM_000251.3(MSH2):c.964G>A(p.Gly322Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G322D) has been classified as Benign.
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.964G>A | p.Gly322Ser | missense_variant | 6/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.964G>A | p.Gly322Ser | missense_variant | 6/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251428Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135888
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460174Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2AN XY: 726560
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 08, 2023 | This missense variant replaces glycine with serine at codon 322 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with uterine cancer (PMID: 29684080). This variant has been identified in 5/251428 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 | curation | Sema4, Sema4 | Jan 26, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 03, 2023 | 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 | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Feb 22, 2023 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 27, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a personal history of uterine cancer (Yehia et al., 2018); Published functional studies suggest no damaging effect: mismatch repair (MMR) function similar to wildtype (Jia et al., 2020); This variant is associated with the following publications: (PMID: 27720647, 18822302, 21120944, 29684080, 33357406) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 26, 2017 | Variant summary: The MSH2 c.964G>A (p.Gly322Ser) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 2/121144 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. - |
Lynch syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 12, 2023 | - - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 27, 2023 | This missense variant replaces glycine with serine at codon 322 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with uterine cancer (PMID: 29684080). This variant has been identified in 5/251428 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. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at