ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.944G>T (p.Gly315Val) (rs202026056)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000781990 SCV000920446 likely benign Lynch syndrome 2018-12-19 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability < 0.05 (0.009)
GeneDx RCV000034560 SCV000149459 likely benign not provided 2020-08-03 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 10422993, 24082139, 22703879, 19690142, 25559809, 25203624, 26976419, 27600092, 27720647, 32849802)
Invitae RCV001082682 SCV000254432 benign Hereditary nonpolyposis colorectal neoplasms 2020-11-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000491220 SCV000580560 benign Hereditary cancer-predisposing syndrome 2016-03-21 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034560 SCV000601496 likely benign not provided 2020-07-30 criteria provided, single submitter clinical testing
Color Health, Inc RCV000491220 SCV000685141 likely benign Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034560 SCV000043337 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 RCV001355677 SCV001550629 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The MSH2 p.Gly315Val variant was identified in 6 of 3350 proband chromosomes (frequency: 0.002) from individuals or families with Lynch Syndrome, colon cancer, or breast cancer and was not identified in 172 control chromosomes from healthy individuals (Gonzalez-Garay 2013, Johnston 2012, Mueller 2009, Pillar 2015, Syngal 1999, Tung 2016). The variant was also identified in dbSNP (ID: rs202026056) as "With Uncertain significance allele", and in ClinVar (classified as benign by Invitae, Ambry Genetics; as likely benign by GeneDx, Quest Diagnostics Nichols Institute San Juan Capistrano; as uncertain significance by Color Genomics and Biesecker Lab/Human Development Section, National Institutes of Health). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or in Insight Hereditary Tumors Database. The variant was identified in control databases in 55 of 277094 chromosomes at a frequency of 0.0002 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: Other in 1 of 6464 chromosomes (freq: 0.000155), European in 3 of 126640 chromosomes (freq: 0.00002), Ashkenazi Jewish in 21 of 10152 chromosomes (freq: 0.002), and South Asian in 30 of 30778 chromosomes (freq: 0.001), while the variant was not observed in the African, Latino, East Asian, and Finnish populations. The p.Gly315 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 p.Gly315Val variant occurs in the first three bases of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.

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