Submissions for variant NM_000179.3(MSH6):c.1814C>G (p.Thr605Ser)

gnomAD frequency: 0.00006  dbSNP: rs587781616

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129705	SCV000184506	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-17	criteria provided, single submitter	clinical testing	The p.T605S variant (also known as c.1814C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 1814. The threonine at codon 605 is replaced by serine, an amino acid with similar properties. This alteration has also been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). Additionally, this alteration was seen in 0/732 breast cancer patients, 0/189 colorectal cancer patients and 1/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). This variant was also reported in 2/60,466 breast cancer cases and in 3/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly conserved in available vertebrate species. 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.
GeneDx	RCV000587763	SCV000211349	uncertain significance	not provided	2023-08-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history of breast or unspecified cancer as well as in unaffected control individuals (Rizzolo et al., 2019; Tsaousis et al., 2019; Akcay et al., 2020; Li et al., 2020; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 31159747, 31391288, 30613976, 33471991, 17531815, 21120944, 32658311)
Invitae	RCV000200701	SCV000254282	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129705	SCV000685228	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-14	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 605 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 31159747), and an individual suspected of having Lynch syndrome (PMID: 31391288). This variant has been identified in 15/281884 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587763	SCV000695796	uncertain significance	not provided	2017-08-08	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.1814C>G (p.Thr605Ser) variant located in the DNA mismatch repair protein MutS, connector domain (via InterPro) involves the alteration of a conserved nucleotide and 3/5 in silico tools predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 15/276888 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000103 (13/126470). This frequency is comparable to the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421), suggesting this variant could be a rare benign polymorphism found in population(s) of European (Non-Finnish) origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Although, multiple clinical diagnostic laboratories and a reputable database classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
GeneKor MSA	RCV000129705	SCV000822061	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000708871	SCV000837888	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587763	SCV000889461	uncertain significance	not provided	2019-04-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765684	SCV000897026	uncertain significance	Endometrial carcinoma; Mismatch repair cancer syndrome 1; Lynch syndrome 5	2018-10-31	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000708871	SCV004840152	uncertain significance	Lynch syndrome	2023-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 605 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 31159747), and an individual suspected of having Lynch syndrome (PMID: 31391288). This variant has been identified in 15/281884 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.