ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1054G>A (p.Val352Ile) (rs730881787)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656893 SCV000211271 uncertain significance not provided 2017-05-24 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1054G>A at the cDNA level, p.Val352Ile (V352I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in an endometrial tumor (Geurts-Giele 2014). MSH6 Val352Ile was observed at an allele frequency of 0.03% (5/16,504) in individuals of South Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. MSH6 Val352Ile occurs at a position that is not conserved and is located within the nuclear localization signal (Gassman 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether MSH6 Val352Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160662 SCV000212768 likely benign Hereditary cancer-predisposing syndrome 2018-04-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000656893 SCV000230040 uncertain significance not provided 2014-11-20 criteria provided, single submitter clinical testing
Invitae RCV000656893 SCV000283697 likely benign not provided 2019-03-01 criteria provided, single submitter clinical testing
Mendelics RCV000708862 SCV000837876 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000160662 SCV000902890 likely benign Hereditary cancer-predisposing syndrome 2016-06-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780471 SCV000917744 likely benign not specified 2019-05-17 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1054G>A (p.Val352Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.4e-05 in 282596 control chromosomes, predominantly at a frequency of 0.00029 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. The variant, c.1054G>A, has been reported in the literature in individuals affected with breast cancer or colon cancer (Tung_2014, Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant twice as likely benign and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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