ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.208G>A (p.Ala70Thr)

gnomAD frequency: 0.00001  dbSNP: rs587778522
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000771511 SCV000904000 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-14 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 70 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 not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 2/221594 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.
Invitae RCV000808087 SCV000948178 likely benign Hereditary nonpolyposis colorectal neoplasms 2023-12-20 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000121558 SCV002071981 uncertain significance not specified 2021-11-21 criteria provided, single submitter clinical testing This sequence change does not appear to have been previously described in individuals with MSH2-related disorders. This sequence change has been described in the gnomAD database in two individuals which corresponds to a population frequency of 0.00090% (dbSNP rs587778522). The p.Ala70Thr change affects a poorly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Ala70Thr substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Ala70Thr change remains unknown at this time.
Ambry Genetics RCV000771511 SCV002730235 uncertain significance Hereditary cancer-predisposing syndrome 2021-06-16 criteria provided, single submitter clinical testing The p.A70T variant (also known as c.208G>A), located in coding exon 1 of the MSH2 gene, results from a G to A substitution at nucleotide position 208. The alanine at codon 70 is replaced by threonine, an amino acid with similar properties. In one study, this variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant was also identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS One, 2014 Apr;9:e94554). This amino acid position is 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.
PreventionGenetics, part of Exact Sciences RCV004528832 SCV004107434 uncertain significance MSH2-related disorder 2023-05-11 criteria provided, single submitter clinical testing The MSH2 c.208G>A variant is predicted to result in the amino acid substitution p.Ala70Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0052% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47630538-G-A). High throughput MSH2 missense variant testing suggested that this variant is functionally neutral (Jia, X et al. 2021. PubMed:33357406). This variant has conflicting interpretations in clinvar ranging from likely benign to variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/134841/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health RCV003997347 SCV004832050 uncertain significance Lynch syndrome 2023-06-26 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 70 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 not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 2/221594 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.
ITMI RCV000121558 SCV000085752 not provided not specified 2013-09-19 no assertion provided reference population

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