ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.746_747delAGinsCC (p.Gln249Pro) (rs587782209)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617132 SCV000185793 uncertain significance Cardiovascular phenotype 2018-04-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000130885 SCV000686555 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-06 criteria provided, single submitter clinical testing
GeneDx RCV000586288 SCV000565584 uncertain significance not provided 2018-12-11 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.746_747delAGinsCC at the cDNA level and p.Gln249Pro (Q249P) at the protein level. The surrounding sequence is CAGC[delAG][insCC]CAGA. This in-frame deletion and insertion results in the missense change of a Glutamine to a Proline (CAG>CCC). SMAD4 Gln249Pro has been observed in an individual with clinical features of hereditary hemorrhagic telangiectasia and a family history suggestive of juvenile polyposis syndrome (Schwenter 2012). This variant has also been reported in an individual with prostate cancer (Isaacsson Velho 2018). This variant was observed at an allele frequency of 0.23% (21/10,368) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This variant is located within the linker domain (Howe 2004, Calva-Cerqueira 2009, Massague 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear if SMAD4 Gln249Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586288 SCV000698580 likely benign not provided 2017-07-14 criteria provided, single submitter clinical testing Variant summary: The SMAD4 c.746_747delinsCC (p.Gln249Pro) variant causes a missense change in a run of 3 Glns. This variant was found in 40/277204 control chromosomes (gnomAD) at a frequency of 0.0001443, which is approximately 72 times the estimated maximal expected allele frequency of a pathogenic SMAD4 variant (0.000002), suggesting this variant is likely a benign polymorphism. Multiple publications have cited this variant across varying phenotypes including one study, Dudley_2016, that was evaluating high-risk neoplasia or malignancy using bile duct brushing, which identified the variant to co-occur with two additional pathogenic variants, KRAS c.35G>T and TP53 c.524G>A. As the frequency of occurrence of KRAS codon 12 and 13 mutations in sporadic colorectal adenocarcinomas is well documented, the possibility of a sporadic (non-inherited) etiology of cancer in this reported patient cannot be excluded as matched germline analysis was not performed in this study. However, this finding decreases the likelihood of contribution of this SMAD4 variant towards the etiology and pathogenesis of cancer in this reported patient. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as likely benign.
Invitae RCV000198702 SCV000254845 likely benign Juvenile polyposis syndrome 2018-01-09 criteria provided, single submitter clinical testing

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