ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3801+5G>A (rs201080919)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166530 SCV000217331 likely benign Hereditary cancer-predisposing syndrome 2017-11-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: RNA Studies
Invitae RCV000524188 SCV000262055 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-22 criteria provided, single submitter clinical testing This sequence change falls in intron 8 of the MSH6 gene. It does not directly change the encoded amino acid sequence of the MSH6 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs201080919, ExAC 0.02%). This variant has been reported in individuals affected with breast cancer (PMID: 26845104, 26976419), colorectal cancer (PMID: 28135145), and an individual referred for Lynch syndrome genetic testing (PMID: 25318351). This variant is also known as IVS8+5G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 186876). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
University of Washington Department of Laboratory Medicine,University of Washington RCV000203730 SCV000266086 likely benign Lynch syndrome 2016-12-20 criteria provided, single submitter clinical testing Communication from other laboratories about other patients with this variant and no family history of colorectal cancer. Splicing anlaysis indicates 95% full length product.
GeneDx RCV000587152 SCV000279111 uncertain significance not provided 2018-04-03 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3801+5G>A or IVS8+5G>A and consists of a G>A nucleotide substitution at the +5 position of intron 8 of the MSH6 gene. In silico analyses, which include splice predictors and evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging. This variant has been observed in an individual with colorectal cancer, in two individuals with breast cancer, and in at least one other individual referred for hereditary cancer testing (Yorczyk 2015, Shirts 2016, Tung 2016, Yurgelun 2017). MSH6 c.3801+5G>A was observed at an allele frequency of 0.05% (5/9,848) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether MSH6 c.3801+5G>A is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000203730 SCV000430980 uncertain significance Lynch syndrome 2016-06-14 criteria provided, single submitter clinical testing
Counsyl RCV000411771 SCV000488861 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-09-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587152 SCV000695890 uncertain significance not provided 2017-03-30 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3801+5G>A variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant weakens or eliminates the 3' splicing donor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 7/121198 control chromosomes at a frequency of 0.0000578, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). This variant has been reported in at least one patient with breast cancer without evidence supporting causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, except one clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as VUS.
Color RCV000166530 SCV000902693 likely benign Hereditary cancer-predisposing syndrome 2016-12-21 criteria provided, single submitter clinical testing

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