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

gnomAD frequency: 0.00003  dbSNP: rs537604099

Total submissions: 7

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001201355	SCV000551252	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-10-03	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
All of Us Research Program, National Institutes of Health	RCV000469296	SCV004836085	uncertain significance	Lynch syndrome	2024-05-14	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 affected with colorectal or endometrial cancer (PMID: 31391288), and in an individual affected with breast cancer (PMID: 25186627). 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.