Submissions for variant NM_000179.3(MSH6):c.3014G>A (p.Arg1005Gln)

gnomAD frequency: 0.00001  dbSNP: rs587782324

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131231	SCV000186186	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-18	criteria provided, single submitter	clinical testing	The p.R1005Q variant (also known as c.3014G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 3014. The arginine at codon 1005 is replaced by glutamine, an amino acid with highly similar properties. This alteration is observed homozygous in an individual whose clinical features are consistent with constitutional mismatch repair deficiency (CMMRD) syndrome (Ambry internal data). This alteration is observed in an individual whose endometrial tumor demonstrated loss of MSH6 expression on immunohistochemistry (IHC); however, this alteration is also observed in an individual whose ovarian tumor demonstrated normal mismatch repair protein expression on IHC (Ambry internal data). 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.
Color Diagnostics, LLC DBA Color Health	RCV000131231	SCV000690308	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1005 of the MSH6 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sporadic colon cancer (UMD: http://139.124.156.133/4D_molecules/UMD012708.html, PMID: 10612827). This variant has been identified in 2/241392 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	RCV000764426	SCV000895483	uncertain significance	Endometrial carcinoma; Mismatch repair cancer syndrome 1; Lynch syndrome 5	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV001060704	SCV001225408	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1005 of the MSH6 protein (p.Arg1005Gln). This variant is present in population databases (rs587782324, gnomAD 0.009%). This missense change has been observed in individuals with clinical features of Lynch syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 142232). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH6 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290553	SCV001478622	uncertain significance	not specified	2021-01-30	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3014G>A (p.Arg1005Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-06 in 209994 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3014G>A has been reported in the literature in individuals affected with colorectal cancer (example, Li_2020). A recent study reporting tumor characteristic likelihood ratio (TCLR) in combination with in silico predictors and a multifactorial variant prediction model that included allele frequency, co-occurrence, co-segregation, clinical and family history information, classified this variant as uncertain significance (Li_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003998092	SCV004834467	uncertain significance	Lynch syndrome	2023-09-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1005 of the MSH6 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sporadic colon cancer (UMD: http://139.124.156.133/4D_molecules/UMD012708.html, PMID: 10612827). This variant has been identified in 2/241392 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.