Submissions for variant NM_000179.3(MSH6):c.1754T>C (p.Leu585Pro)

dbSNP: rs587779220

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000219463	SCV000279553	likely pathogenic	not provided	2020-09-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: deficient in mismatch repair activity and reduction of MSH6 protein (Kantelinen 2012); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Kantelinen 2012, Frolova 2015, Haraldsdottir 2017, Carter 2018); Common founder variant in the Icelandic population (Haraldsdottir 2017); This variant is associated with the following publications: (PMID: 22949387, 25617771, 22581703, 28466842, 29887214, 30322717, 29485237, 32719484)
Invitae	RCV000791380	SCV000551070	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 585 of the MSH6 protein (p.Leu585Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 22581703, 23773459, 25617771, 30877237). ClinVar contains an entry for this variant (Variation ID: 89220). 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 95%. Experimental studies have shown that this missense change affects MSH6 function (PMID: 22581703). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000491054	SCV000580096	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-30	criteria provided, single submitter	clinical testing	The p.L585P variant (also known as c.1754T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 1754. The leucine at codon 585 is replaced by proline, an amino acid with similar properties. This alteration has been reported in conjunction with another MSH6 alteration (p.S677T) in an individual diagnosed with colon cancer at age 38 whose tumor showed high microsatellite instability and intact MLH1, MSH2, and PMS2 staining on immunohistochemistry (IHC), but inconclusive MSH6 staining. Furthermore, in vitro MMR assays showed that the p.L585P alteration displayed deficient MMR activity, while the second variant, p.S677T, displayed proficient MMR activity (Kantelinen J et al. Hum Mutat. 2012 Aug;33(8):1294-301). In addition, this alteration has been detected in several individuals diagnosed with colorectal and/or endometrial cancer whose tumor results revealed loss of MSH6 on IHC (Ambry internal data; Frolova AI et al. Gynecol. Oncol. 2015 Apr;137:7-13; Haraldsdottir S et al. Nat Commun. 2017 May;8:14755; Kral J et al. Oncol Lett, 2023 Jun;25:216). This alteration has also been identified in a cohort of 4,439 women with ovarian cancer (Carter NJ et al. Gynecol. Oncol., 2018 12;151:481-488). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. In addition, based on internal structural analysis, p.L585P is predicted to strongly perturb the structure of the ATPase domain; however, the local sensitivity of the region has not been well characterized (Warren JJ et al. Mol. Cell. 2007 May; 26(4):579-92). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this alteration is likely to be pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000074683	SCV000887368	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH6 NM_000179.2:c.1754T>C has a 96.7% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290557	SCV001478629	likely pathogenic	Hereditary nonpolyposis colon cancer	2024-01-16	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1754T>C (p.Leu585Pro) results in a non-conservative amino acid change located in the connector domain (IPR007860) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250308 control chromosomes (gnomAD). c.1754T>C has been reported in the literature in individuals affected or suspected to be affected with Hereditary Nonpolyposis Colorectal Cancer (Lynch Sydrome; e.g., Kantelinin_2012, Cushman-Vokoun_2013, Haraldsdottir_2017, Pearlman_2019, Svensson_2022). However, no conclusive evidence for causality, such as cosegregation with disease in family studies, has been reported in these publications; therefore this evidence does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. The variant has also been reported in an individual with endometrial cancer who had a family history of Lynch Syndrome-associated cancers and whose tumor tested MSH6-negative by IHC staining (e.g. Frolova_2015), a second individual with endometrial cancer (e.g., Kral_2023), and an individual with ovarian cancer (e.g. Carter_2018). At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant impairs mismatch repair activity and results in unstable MSH6 protein when studied in vitro (e.g. Kantelinin_2012). The following publications have been ascertained in the context of this evaluation (PMID: 30322717, 23773459, 25617771, 28466842, 22581703, 37153042, 30877237, 29887214, 35430768). ClinVar contains an entry for this variant (Variation ID: 89220). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV003450930	SCV004185555	likely pathogenic	Lynch syndrome 5	2023-08-15	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 22581703]. This variant is expected to disrupt protein structure [Myriad internal data].
Baylor Genetics	RCV003128136	SCV004198149	likely pathogenic	Endometrial carcinoma	2022-06-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000219463	SCV004221155	pathogenic	not provided	2023-01-16	criteria provided, single submitter	clinical testing	The MSH6 c.1754T>C (p.Leu585Pro) variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with colorectal cancer (PMID: 30877237 (2019), 22581703 (2012)) and ovarian/endometrial cancer (PMIDs: 30322717 (2018), 25617771 (2015)). It has also been described as a founder mutation associated with colorectal and endometrial cancer risk in Iceland (PMID: 28466842 (2017)). In addition, functional studies indicate this variant had deleterious effects on MSH6 protein stability and DNA mismatch repair activity (PMID: 22581703 (2012)). Based on the available information, this variant is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004537273	SCV004715445	likely pathogenic	MSH6-related disorder	2023-11-13	criteria provided, single submitter	clinical testing	The MSH6 c.1754T>C variant is predicted to result in the amino acid substitution p.Leu585Pro. This variant was reported in an individual with hereditary nonpolyposis colorectal cancer (Kantelinen J et al 2012. PubMed ID: 22581703). In a large study from Iceland, the c.1754T>C variant was detected as a germline variant in 9 patients with mismatch repair deficiency colorectal cancer (Table 1 in Haraldsdottir et al 2017. PubMed ID: 28466842). This variant was also reported in an individual with ovarian cancer (Carter NJ et al 2018. PubMed ID: 30322717) and a patient with endometrial cancer with a family history of Lynch Syndrome-associated cancers (Frolova AI et al 2015. PubMed ID: 25617771). In vitro mismatch repair assays indicate this variant impacts protein function (Kantelinen J et al 2012. PubMed ID: 22581703). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org) and is reported by most labs in ClinVar as likely pathogenic or pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/89220/). This variant is interpreted as likely pathogenic.
CZECANCA consortium	RCV003128136	SCV003804331	likely pathogenic	Endometrial carcinoma	2023-02-21	no assertion criteria provided	clinical testing
deCODE genetics, Amgen	RCV003450930	SCV004022208	likely pathogenic	Lynch syndrome 5	2023-07-21	no assertion criteria provided	research	The variant NM_000179.3:c.1754T>C (chr2:47799737) in MSH6 was detected in 34 heterozygotes out of 58K WGS Icelanders (MAF= 0,029%). Following imputation in a set of 166K Icelanders (102 imputed heterozygotes) we observed an association with colorectal cancer using 4991 cases and 314812 controls (OR= 9.62, P= 9.55e-12). This variant has been reported in ClinVar previously as pathogenic, likely pathogenic and as a variant of uncertain significance. Based on ACMG criteria (PS4, PM2, PP3, PP5) this variant classifies as likely pathogenic.