ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1315C>G (p.Pro439Ala)

dbSNP: rs786203116
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487340 SCV000571801 uncertain significance not provided 2024-02-12 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a neutral effect: demonstrates sensitivity to 6-TG and mismatch repair (MMR) function similar to wild-type (PMID: 33357406); This variant is associated with the following publications: (PMID: 33357406, 36243179)
Ambry Genetics RCV001010926 SCV001171191 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-19 criteria provided, single submitter clinical testing The p.P439A variant (also known as c.1315C>G), located in coding exon 8 of the MSH2 gene, results from a C to G substitution at nucleotide position 1315. The proline at codon 439 is replaced by alanine, an amino acid with highly similar properties. In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This amino acid position is highly conserved on limited sequence alignment. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Cancer Genomics Group, Japanese Foundation For Cancer Research RCV001030709 SCV001193631 uncertain significance Hereditary breast ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV001851231 SCV002136346 likely benign Hereditary nonpolyposis colorectal neoplasms 2023-12-12 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001010926 SCV004356677 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-04 criteria provided, single submitter clinical testing This missense variant replaces proline with alanine at codon 439 of the MSH2 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). This variant has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 2/250892 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.
All of Us Research Program, National Institutes of Health RCV004003373 SCV004837120 uncertain significance Lynch syndrome 2024-02-05 criteria provided, single submitter clinical testing This missense variant replaces proline with alanine at codon 439 of the MSH2 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). This variant has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 2/250892 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.
Fulgent Genetics, Fulgent Genetics RCV005027555 SCV005661117 uncertain significance Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2 2024-04-13 criteria provided, single submitter clinical testing

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