ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2667G>T (p.Gln889His) (rs149945495)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000034496 SCV000149302 likely benign not provided 2021-01-22 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26689913, 27060149, 22703879, 23621914, 28503720, 28767289, 32659497)
Ambry Genetics RCV000115393 SCV000185458 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-16 criteria provided, single submitter clinical testing The p.Q889H variant (also known as c.2667G>T), located in coding exon 4 of the MSH6 gene, results from a G to T substitution at nucleotide position 2667. The glutamine at codon 889 is replaced by histidine, an amino acid with highly similar properties. This alteration was detected in an African American woman diagnosed with breast cancer under 40, whose family history includes a paternal grandfather with pancreatic cancer (Rummel SK et al. Breast Cancer Res. Treat. 2017 Aug;164:593-601). This alteration was also detected in an African American patient diagnosed with pancreatic ductal adenocarcinoma at 38, whose father had a history of colorectal cancer​ (Shindo K et al. J. Clin. Oncol., 2017 Oct;35:3382-3390). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001080247 SCV000254299 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 criteria provided, single submitter clinical testing
Counsyl RCV000410628 SCV000488488 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-04-14 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000235185 SCV000595854 uncertain significance not specified 2017-01-12 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034496 SCV000601536 likely benign not provided 2019-01-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115393 SCV000685307 likely benign Hereditary cancer-predisposing syndrome 2020-12-22 criteria provided, single submitter clinical testing
Mendelics RCV000708879 SCV000837901 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000410628 SCV001761617 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2021-07-22 criteria provided, single submitter clinical testing The MSH6 c.2667G>T (p.Gln889His) missense change has a maximum subpopulation frequency of 0.15% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-48027789-G-T). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in an African American woman diagnosed with breast cancer before 40 years whose family history includes a paternal grandfather with pancreatic cancer (PMID: 28503720) and at least one individual with pancreatic ductal adenocarcinoma (PMID: 28767289, 32659497). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: no criteria met.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034496 SCV000043359 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000034496 SCV001549812 uncertain significance not provided no assertion criteria provided clinical testing The MSH6 p.Gln889His variant was identified in 3 of 12170 proband chromosomes (frequency: 0.0003) from individuals or families with atherosclerosis or breast cancer (Johnston 2012, Lu 2015, Rummel 2017). The variant was also identified in dbSNP (ID: rs149945495) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and six other submitters), and in MutDB, databases. The variant was not identified in COGR, Cosmic, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors, databases. The variant was identified in control databases in 36 of 276358 chromosomes at a frequency of 0.0001 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 35 of 23982 chromosomes (freq: 0.002), Other in 1 of 6448 chromosomes (freq: 0.0002), while the variant was not observed in the Latino, European, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Gln889 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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