ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.1215C>T (p.His405=)

gnomAD frequency: 0.00003  dbSNP: rs751732234
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229918 SCV000288869 likely benign Juvenile polyposis syndrome 2024-01-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV002313940 SCV000675137 likely benign Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome 2015-10-14 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health RCV000572344 SCV000686516 likely benign Hereditary cancer-predisposing syndrome 2016-03-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV002479917 SCV002047244 benign not specified 2021-06-06 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000572344 SCV002538294 likely benign Hereditary cancer-predisposing syndrome 2021-09-22 criteria provided, single submitter curation
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001354161 SCV001548704 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The SMAD4 p.His405= variant was identified in 1 of 326 proband chromosomes (frequency: 0.003) from circulating tumour DNA in an individual with pancreatic cancer (Kukita 2018). The variant was identified in dbSNP (rs751732234) as “with likely benign allele” and ClinVar (classified as likely benign by Invitae, Ambry Genetics and Color). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 8 of 282,856 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 3 of 19,948 chromosomes (freq: 0.0002), South Asian in 3 of 30,616 chromosomes (freq: 0.0001), African in 1 of 24,966 chromosomes (freq: 0.00004), and European in 1 of 129,178 chromosomes (freq: 0.000008), while it was not observed in the Latino, Ashkenazi Jewish, Finnish or Other populations. The p.His405= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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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