ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2161A>G (p.Arg721Gly)

gnomAD frequency: 0.00003  dbSNP: rs537604099
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132526 SCV000187623 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-22 criteria provided, single submitter clinical testing The p.R721G variant (also known as c.2161A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2161. The arginine at codon 721 is replaced by glycine, an amino acid with dissimilar properties. This alteration was detected on a 25-gene panel test in a woman of Neareast/Mideast ancestry who was diagnosed with 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.
Invitae RCV001201355 SCV000551252 likely benign Hereditary nonpolyposis colorectal neoplasms 2023-12-27 criteria provided, single submitter clinical testing
Mendelics RCV000469296 SCV000837893 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000132526 SCV000903780 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-23 criteria provided, single submitter clinical testing This missense variant replaces arginine with glycine at codon 721 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 performed for this variant. This variant has been observed in an individual with colorectal or endometrial cancer (PMID: 31391288). This variant has been identified in 5/282358 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.
GeneDx RCV003320574 SCV004025566 uncertain significance not provided 2023-08-08 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; Observed in an individual with breast cancer and family history of cancer (Tung et al., 2015); This variant is associated with the following publications: (PMID: 17531815, 21120944, 31391288, 25186627, 35171259)
Baylor Genetics RCV003462049 SCV004195619 uncertain significance Endometrial carcinoma 2023-08-03 criteria provided, single submitter clinical testing

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