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 2019-01-24 criteria provided, single submitter clinical testing RNA Studies
Invitae RCV000524188 SCV000262055 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-18 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 RCV000411771 SCV000430980 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
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 RCV001260253 SCV000695890 uncertain significance not specified 2020-09-04 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3801+5G>A alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predicts the variant weakens a 5' donor site. Three predict the variant abolishes a 5' splicing donor site. However, RNA studies demonstrate this variant has no abnormal splicing (Karam_2019). The variant allele was found at a frequency of 8.8e-05 in 251178 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer (8.8e-05 vs 0.00014), allowing no conclusion about variant significance. c.3801+5G>A has been reported in the literature in individuals affected with breast cancer, colorectal cancer, Lynch Syndrome as well as in healthy individuals (Shirts_2016, Tung_2016, Yorczyk_2015, Yurgelun_2017, Karam_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variants have been reported internally (RB1 c.1399C>T, p.Arg467X; BRCA1 c.2411_2412delAG, p.Gln804LeufsX5), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (4x) and likely benign (3x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Color RCV000166530 SCV000902693 likely benign Hereditary cancer-predisposing syndrome 2016-12-21 criteria provided, single submitter clinical testing

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