ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3151G>A (p.Val1051Ile) (rs576269342)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001257068 SCV000166225 benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000132157 SCV000187231 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-19 criteria provided, single submitter clinical testing The p.V1051I variant (also known as c.3151G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 3151. The valine at codon 1051 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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 Hereditary nonpolyposis colorectal cancer type 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.
PreventionGenetics,PreventionGenetics RCV000588824 SCV000805875 uncertain significance not provided 2017-01-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132157 SCV000902696 benign Hereditary cancer-predisposing syndrome 2016-05-12 criteria provided, single submitter clinical testing
Mendelics RCV000408980 SCV001135829 likely benign Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030498 SCV001193652 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
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.

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