Submissions for variant NM_000179.3(MSH6):c.3151G>A (p.Val1051Ile)

dbSNP: rs576269342

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001257068	SCV000166225	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000132157	SCV000187231	benign	Hereditary cancer-predisposing syndrome	2021-06-03	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000588824	SCV000211312	likely benign	not provided	2021-04-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23047549, 28873162, 31386297, 31660093)
Counsyl	RCV000408980	SCV000488006	uncertain significance	Lynch syndrome 5	2015-12-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588824	SCV000695839	benign	not provided	2016-04-29	criteria provided, single submitter	clinical testing	Variant summary: The variant of interest causes a missense change involving a conserved nucleotide with 4/5 in silico programs predicting a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 107/119266 (1/1114), predominantly in the South Asian cohort, 106/16430 (1/154), which exceeds the predicted maximum expected allele frequency for a pathogenic MSH6 variant of 1/7037. Therefore, suggesting that the variant of interest is a common polymorphism found in population(s) of South Asian origin. The variant of interest was observed in affected individuals via a publication, although with limited information (ie lack of co-occurrence/co-segregation data). Multiple reputable clinical laboratories cite the variant with a classification of "uncertain significance," however, it should be noted that these classifications were evaluated previous to ExAC data being available. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign.
Color Diagnostics, LLC DBA Color Health	RCV000132157	SCV000902696	benign	Hereditary cancer-predisposing syndrome	2016-05-12	criteria provided, single submitter	clinical testing
Mendelics	RCV000408980	SCV001135829	likely benign	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030498	SCV001193652	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000132157	SCV002535794	likely benign	Hereditary cancer-predisposing syndrome	2021-10-24	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000408980	SCV004019031	benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. 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	RCV001796965	SCV004024798	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492535	SCV004239313	likely benign	Breast and/or ovarian cancer	2022-07-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528840	SCV000805875	likely benign	MSH6-related disorder	2020-07-29	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355067	SCV001549834	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Val1051Ile variant was identified in 2 of 3786 proband chromosomes (frequency: 0.0005) from individuals or families with epithelial ovarian cancer (Pal 2012). The variant was also identified in dbSNP (ID: rs576269342) as "With Uncertain significance allele", ClinVar (classified as benign by Invitae and Integrated Genetics/Laboratory Corporation of America; as likely benign by GeneDx; and as uncertain significance by three submitters), and Cosmic database (2x in upper aerodigestive tract tissue). The variant was not identified in COGR, MutDB, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 218 of 247410 chromosomes (1 homozygous) at a frequency of 0.0009 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: South Asian in 215 of 30590 chromosomes (freq: 0.007) and Other in 3 of 6076 chromosomes (freq: 0.0005); it was not observed in the Ashkenazi Jewish, African, East Asian, Finnish, European, or Latino populations. The p.Val1051 residue is conserved in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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, this variant meets our laboratory's criteria to be classified as benign.