ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.170C>G (p.Pro57Arg)

gnomAD frequency: 0.00001  dbSNP: rs1064793657
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000526386 SCV000624684 likely benign Hereditary nonpolyposis colorectal neoplasms 2023-07-07 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000582708 SCV000690219 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-08 criteria provided, single submitter clinical testing This missense variant replaces proline with arginine at codon 57 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 not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/154666 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.
Ambry Genetics RCV000582708 SCV001173340 uncertain significance Hereditary cancer-predisposing syndrome 2024-04-19 criteria provided, single submitter clinical testing The p.P57R variant (also known as c.170C>G), located in coding exon 1 of the MSH6 gene, results from a C to G substitution at nucleotide position 170. The proline at codon 57 is replaced by arginine, an amino acid with dissimilar properties. This alteration was reported in a cohort of 464 individuals with a family history of pancreatic cancer (Abe T et al. J Clin Oncol, 2019 05;37:1070-1080). This variant was also observed in an individual with early onset-breast cancer amongst a cohort of 1781 non-Ashkenazi Jewish individuals undergoing BRCA1/2 gene testing based on a personal history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV003320671 SCV004025551 uncertain significance not provided 2023-08-02 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with personal and/or family history of breast, pancreatic, and other cancers (Tung et al., 2015; Abe et al., 2019); This variant is associated with the following publications: (PMID: 25186627, 30883245)
Baylor Genetics RCV004568703 SCV005054942 uncertain significance Endometrial carcinoma 2024-02-05 criteria provided, single submitter clinical testing

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