Submissions for variant NM_000179.3(MSH6):c.2561A>T (p.Lys854Met)

gnomAD frequency: 0.00036  dbSNP: rs34374438

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001083699	SCV000166221	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129191	SCV000183929	likely benign	Hereditary cancer-predisposing syndrome	2020-10-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000585210	SCV000211298	likely benign	not provided	2021-03-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19389263, 14520694, 24728327, 16813607, 21153778, 23047549, 25637381, 15872200, 11470537, 26333163, 26898890, 25151137, 26530882, 23621914, 28767289, 29212164, 25479140, 29684080, 29368341, 28873162, 17531815)
Color Diagnostics, LLC DBA Color Health	RCV000129191	SCV000537549	likely benign	Hereditary cancer-predisposing syndrome	2020-04-06	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000121574	SCV000539709	uncertain significance	not specified	2016-06-23	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 5 VUS (including expert panel, no evidence supporting pathogenicity since expert classification)
CeGaT Center for Human Genetics Tuebingen	RCV000585210	SCV000692987	uncertain significance	not provided	2017-08-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121574	SCV000695818	benign	not specified	2021-06-06	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2561A>T (p.Lys854Met) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 249996 control chromosomes, predominantly at a frequency of 0.0017 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2561A>T has been reported in the literature in individuals affected with cancer including pancreatic cancer, Lynch Syndrome, ovarian cancer and prostate cancer (Isaacsson Velho_2018, Shindo_2017, Grant_2015, Pal_2012, Suchy_2006, Hampel_2005, Peterlongo_2003, Ohmiya_2001). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. In one study examining non-medullary thyroid cancer, the variant of interest was detected in only one of the two affected individuals from a single family (Yu_2015). At-least one co-occurrence with a pathogenic variant has been observed at our laboratory (BRCA2 c.1813delA, p.Ile605fsX9; internal testing), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in a complete in vitro MMR (mismatch repair) activity (CIMRA) assay that was developed to quantify the functional activity of variants in MMR genes (Drost_2020). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the predominant evidence supporting a neutral outcome as outlined above, the variant was re-classified as benign.
PreventionGenetics, part of Exact Sciences	RCV004528270	SCV000805868	uncertain significance	MSH6-related disorder	2024-02-16	criteria provided, single submitter	clinical testing	The MSH6 c.2561A>T variant is predicted to result in the amino acid substitution p.Lys854Met. This variant has been reported in individuals with ovarian cancer (Pal et al. 2012, Table S1, PubMed ID: 23047549), colon cancer, melanoma (Ohmiya et al. 2001. PubMed ID: 11470537; Suchy et al. 2006. PubMed ID: 16813607), pancreatic cancer (Table S1, Shindo et al. 2017. PubMed ID: 28767289) and prostate cancer (Table S1, Isaacsson Velho et al. 2018. PubMed ID: 29368341), but in all cases was classified as a variant of uncertain significance. This variant was also identified in an individual from a cohort of healthy individuals (Table S1, Bodian et al. 2014. PubMed ID: 24728327) and has been reported with a frequency of 0.19% among individuals of Ashkenazi Jewish origin in the gnomAD database. In ClinVar, this variant has conflicting interpretations of pathogenicity including benign, likely benign, and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/89289/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Fulgent Genetics, Fulgent Genetics	RCV000764424	SCV000895481	uncertain significance	Endometrial carcinoma; Mismatch repair cancer syndrome 1; Lynch syndrome 5	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000986723	SCV001135821	benign	Lynch syndrome 5	2023-08-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000585210	SCV002046354	likely benign	not provided	2022-10-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129191	SCV002535751	likely benign	Hereditary cancer-predisposing syndrome	2021-01-31	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149719	SCV003838319	likely benign	Breast and/or ovarian cancer	2022-03-11	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000129191	SCV004014954	benign	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing
ITMI	RCV000121574	SCV000085770	not provided	not specified	2013-09-19	no assertion provided	reference population
CSER _CC_NCGL, University of Washington	RCV000148652	SCV000190367	uncertain significance	Colorectal cancer	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353909	SCV000592609	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Lys854Met variant was identified in 6 of 6608 proband chromosomes (frequency: 0.0009) from individuals with colorectal, prostate, pancreatic and ovarian cancer and was present in 1 of 168 control chromosomes (frequency: 0.006) from healthy individuals (Ohmiya 2001, Peterlongo 2003, Pal 2012, Shindo 2017, Grant 2015, Isaacson-Velho). The variant was identified in dbSNP (rs34374438) as “with uncertain significance allele”, ClinVar (classified as uncertain significance by InSiGHT expert panel (2013), Ambry Genetics, GeneDx, and 8 other submitters and likely benign by Invitae and 1 other submitter) and UMD-LSDB (observed 1x). The variant was identified in control databases in 102 of 276,122 chromosomes at a frequency of 0.0004, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 12 of 23,992 chromosomes (freq: 0.0005), Other in 2 of 6446 chromosomes (freq: 0.0003), Latino in 10 of 34,336 chromosomes (freq: 0.0003), European in 13 of 125,966 chromosomes (freq: 0.0001), Ashkenazi Jewish in 24 of 10,104 chromosomes (freq: 0.002), East Asian in 31 of 18,844 chromosomes (freq: 0.002), and South Asian in 10 of 30,740 chromosomes (freq: 0.0003); it was not observed in the Finnish population. This variant was identified by our laboratory with a co-occurring, pathogenic variant in MSH2 (c.1786_1788del, p.Asn596del) increasing the likelihood the c.2561A>T variant may not have clinical significance. The p.Lys854 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
True Health Diagnostics	RCV000129191	SCV000805272	uncertain significance	Hereditary cancer-predisposing syndrome	2018-04-27	no assertion criteria provided	clinical testing
Ding PR Lab, Sun Yat-sen University Cancer Center	RCV001093694	SCV001250878	uncertain significance	Lynch syndrome 1		no assertion criteria provided	clinical testing