Submissions for variant NM_000179.3(MSH6):c.2398G>C (p.Val800Leu)

gnomAD frequency: 0.00014  dbSNP: rs61748083

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000680176	SCV000107953	likely benign	Lynch syndrome 1	2018-06-13	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability < 0.05 (0.028)
GeneDx	RCV000656572	SCV000149298	likely benign	not provided	2018-12-28	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000115389	SCV000185791	likely benign	Hereditary cancer-predisposing syndrome	2020-03-18	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524141	SCV000218910	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000074744	SCV000266206	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000409574	SCV000487846	uncertain significance	Lynch syndrome 5	2015-11-24	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000212665	SCV000539702	uncertain significance	not specified	2016-03-28	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: 3 papers, all describe as VUS/non-pathogenic; ExAC: 2/11540 Latino chromosomes
GeneKor MSA	RCV000115389	SCV000822062	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115389	SCV000902678	likely benign	Hereditary cancer-predisposing syndrome	2015-12-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212665	SCV000917771	likely benign	not specified	2024-08-30	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2398G>C (p.Val800Leu) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 250774 control chromosomes, predominantly at a frequency of 0.00017 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database higher than the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014). c.2398G>C has been reported in the literature in individuals affected with ovarian cancer (Pal_2012), renal cell carcinoma (Lu_2015), Breast Cancer (Wang_2018) and colorectal cancer (Kim_2004, Kolodner_1999, Shirts_2015), and in one report with positive segregation data, although the number of affected individuals in the family was not reported (Liccardo_2017). Some reports classified the variant as uncertain significance (example: Murphy_2022 and Tsaousis_2019). Co-occurrence with other pathogenic variant(s) have been reported (BRCA1 c.1252G>T, p.Glu418Ter), providing supporting evidence for a benign role for the variant (Wang_2018). At least one publication reports experimental evidence evaluating an impact on protein function. This variant had 91.8% activity in an in vitro MMR activity (CIMRA) assay supporting a benign role for this variant (Drost_2020). The following publications have been ascertained in the context of this evaluation (PMID: 10537275, 15340264, 22290698, 23047549, 23621914, 26689913, 26845104, 28481244, 30982232, 31159747, 31965077, 35128723). ClinVar contains an entry for this variant (Variation ID: 89279). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000409574	SCV001135818	benign	Lynch syndrome 5	2023-08-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212665	SCV001158690	uncertain significance	not specified	2019-05-07	criteria provided, single submitter	clinical testing	The MSH6 c.2398G>C; p.Val800Leu variant (rs61748083) is reported in the literature in individuals with colorectal cancer or ovarian cancer (Kim 2004, Kolodner 1999, Pal 2012, Shirts 2016), but is also reported in a healthy control (Kolodner 1999). This variant is reported in ClinVar (Variation ID: 89279). It is found in the general population with an overall allele frequency of 0.009% (26/282172 alleles) in the Genome Aggregation Database. The valine at codon 800 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Kim JC et al. Genotyping possible polymorphic variants of human mismatch repair genes in healthy Korean individuals and sporadic colorectal cancer patients. Fam Cancer. 2004;3(2):129-37. Kolodner RD et al. Germ-line msh6 mutations in colorectal cancer families. Cancer Res. 1999 Oct 15;59(20):5068-74. Pal T et al. Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. Br J Cancer. 2012 Nov 6;107(10):1783-90. Shirts BH et al. Improving performance of multigene panels for genomic analysis of cancer predisposition. Genet Med. 2016 Oct;18(10):974-81.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000074744	SCV001450733	uncertain significance	Lynch syndrome	2020-10-19	criteria provided, single submitter	clinical testing	The MSH6 c.2398G>C (p.Val800Leu) missense change has a maximum subpopulation frequency of 0.017% in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-48027520-G-C). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. This variant has been reported in individuals with colorectal cancer (PMID: 26845104, 28481244, 10537275). In case control studies, this variant was identified in one control participant and no colorectal cancer patients (PMID: 30267214), while in another case control study the variant was identified at a similar frequency in colorectal cancer cases and normal controls (PMID: 10537275). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000656572	SCV002010104	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798252	SCV002042041	uncertain significance	Breast and/or ovarian cancer	2021-04-20	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115389	SCV002535732	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-16	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000409574	SCV004018995	benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212665	SCV005090488	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148650	SCV000190365	uncertain significance	Colorectal cancer	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353412	SCV000592608	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Val800Leu variant was identified in 1 of 558 proband chromosomes (frequency 0.002) from individuals with colorectal cancer (Kim 2004, Kolodner 1999) and was identified in 1 of 1038 control chromosomes (frequency 0.001) from these studies, increasing the likelihood that this may be a low frequency polymorphism. This variant was also identified in dbSNP (ID# rs61748083) “with untested allele”, in the Exome Variant Server ESP Project with a frequency of 0.0002 in European American alleles, and in the HGMD, MutDB, MMR DB, and InSIGHT Colon Cancer databases. The p.Val800 residue is not conserved in mammals and lower organisms, and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein. In addition, two in silico studies which assessed the impact of the variant on protein structure and function predicted this variant was neutral (Ali 2012, Terui 2013). However, this information is not predictive enough to rule out pathogenicity. 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 predicted benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000656572	SCV000778620	uncertain significance	not provided	2018-02-20	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739333	SCV000805864	uncertain significance	MSH6-related disorder	2024-05-24	no assertion criteria provided	clinical testing	The MSH6 c.2398G>C variant is predicted to result in the amino acid substitution p.Val800Leu. This variant has been reported in individuals with a history of ovarian and colorectal cancer (Kolodner et al. 1999. PubMed ID: 10537275; Supplementary Table 1, Pal et al. 2012. PubMed ID: 23047549; Table S1, Shirts et al. 2016. PubMed ID: 26845104), but was also identified in unaffected control cohorts (Kolodner et al. 1999. PubMed ID: 10537275; Supplementary Table 1, Amendola et al. 2015. PubMed ID: 25637381). This variant was reported in a family with colorectal cancer who had negative testing in MLH1 and MSH2, and also reported to segregate with Lynch syndrome phenotypes, although segregation details were not provided (Table 1, Liccardo et al. 2017. PubMed ID: 28481244). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD. MSH6-specific algorithms predict that this variant is neutral (http://structure.bmc.lu.se/PON-MMR2/; Ali et al. 2012. PubMed ID: 22290698). This variant has conflicting evidence in ClinVar including interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/89279/?new_evidence=false). Taken together, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.