Submissions for variant NM_005359.6(SMAD4):c.746_747delinsCC (p.Gln249Pro)

dbSNP: rs587782209

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002311017	SCV000185793	likely benign	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2021-12-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081446	SCV000254845	likely benign	Juvenile polyposis syndrome	2024-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000586288	SCV000565584	likely benign	not provided	2020-12-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27150160, 22331366, 26596524, 26933808, 29338072, 29368341, 24525918, 30093976)
Color Diagnostics, LLC DBA Color Health	RCV000130885	SCV000686555	likely benign	Hereditary cancer-predisposing syndrome	2019-12-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004562296	SCV001363433	likely benign	not specified	2023-11-27	criteria provided, single submitter	clinical testing	Variant summary: SMAD4 c.746_747delinsCC (p.Gln249Pro) results in a non-conservative amino acid change in the encoded protein sequence. One of two in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251450 control chromosomes. The observed variant frequency is approximately 76 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD4 causing Juvenile Polyposis Syndrome phenotype (2e-06), strongly suggesting that the variant is benign. c.746_747delinsCC has been reported in the literature in sequencing studies of individuals with somatic adenocarcinoma, carcinoma of fallopian tube, ovary or peritonium, and as a germline variant in one patient with HHT (Dudley_2016, Ritterhouse_2016, Schwenter_2012). Specifically, the variant to co-occured with two additional well reported actionable variants, KRAS c.35G>T (p.Gly12Asp) and TP53 c.524G>A (p.Arg175His) in the setting of somatic adenocarcinoma (Dudley_2016). 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. Therefore, none of these report(s) provide unequivocal conclusions about association of the variant with Juvenile Polyposis Syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA1 c.68_69delAG, p.Glu23fsX17), providing further supporting evidence for a benign role. The following publications have been ascertained in the context of this evaluation (PMID: 26596524, 27150160, 22331366, 26933808). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586288	SCV004220364	benign	not provided	2023-09-14	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000586288	SCV001552570	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SMAD4 p.Gln249Pro variant was identified in the 1 of 716 proband chromosomes form a cohort of patients with either, Juvenile polyposis or HHT hereditary hemorrhagic telangiectasia (Schwenter 2012). The patient with the variant had a clinical diagnosis of HHT and also reported a family history consistent with juvenile polyposis. The variant was also identified in tumors including extrauterine Müllerian Carcinomas and Glioblastoma tumor samples (Ritterhouse 2016, Xiu 2016). The variant was also identified in dbSNP (ID: rs587782209) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae and Integrated Genetics/Laboratory Corporation of America; as uncertain significance by three submitters), and in LOVD 3.0 (1x). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Gln249 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs 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. This variant is classified as a variant of uncertain significance.