rs587782209

Positions:

• chr18-51058203-AG-CC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM2 PP2 BP6_Very_Strong

The NM_005359.6(SMAD4):​c.746_747delinsCC​(p.Gln249Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD4 NM_005359.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: 4.65

Genes affected

SMAD4 (HGNC:6770): (SMAD family member 4) This gene encodes a member of the Smad family of signal transduction proteins. Smad proteins are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to transforming growth factor (TGF)-beta signaling. The product of this gene forms homomeric complexes and heteromeric complexes with other activated Smad proteins, which then accumulate in the nucleus and regulate the transcription of target genes. This protein binds to DNA and recognizes an 8-bp palindromic sequence (GTCTAGAC) called the Smad-binding element (SBE). The protein acts as a tumor suppressor and inhibits epithelial cell proliferation. It may also have an inhibitory effect on tumors by reducing angiogenesis and increasing blood vessel hyperpermeability. The encoded protein is a crucial component of the bone morphogenetic protein signaling pathway. The Smad proteins are subject to complex regulation by post-translational modifications. Mutations or deletions in this gene have been shown to result in pancreatic cancer, juvenile polyposis syndrome, and hereditary hemorrhagic telangiectasia syndrome. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMAD4. . Gene score misZ 4.1308 (greater than the threshold 3.09). Trascript score misZ 4.9346 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, generalized juvenile polyposis/juvenile polyposis coli, hereditary hemorrhagic telangiectasia, Myhre syndrome, pulmonary arterial hypertension, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, juvenile polyposis syndrome.
• BP6: Variant 18-51058203-AG-CC is Benign according to our data. Variant chr18-51058203-AG-CC is described in ClinVar as [Likely_benign]. Clinvar id is 142067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD4	NM_005359.6	c.746_747delinsCC	p.Gln249Pro	missense_variant	6/12	ENST00000342988.8	NP_005350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD4	ENST00000342988.8	c.746_747delinsCC	p.Gln249Pro	missense_variant	6/12	5	NM_005359.6	ENSP00000341551	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2020	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) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 14, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 27, 2023

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. -

Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

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. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 23, 2019

- -

Juvenile polyposis syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587782209; hg19: chr18-48584573; COSMIC: COSV61693923;