rs587782209

Variant names:

• chr18-51058203-AG-CC
• rs587782209
• NM_005359.6:c.746_747delAGinsCC

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_005359.6(SMAD4):​c.746_747delAGinsCC​(p.Gln249Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.000145 in 41 alleles, including 0 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q249K) has been classified as Likely benign.

• Frequency: GnomAD MNV: 𝑓 0.00014 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
• Publications: 10 publications found

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]

SMAD4 Gene-Disease associations (from GenCC):

• juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, G2P, PanelApp Australia
• Myhre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• generalized juvenile polyposis/juvenile polyposis coli

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• juvenile polyposis syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary hemorrhagic telangiectasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pulmonary arterial hypertension

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000267699 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant 18-51058203-AG-CC is Benign according to our data. Variant chr18-51058203-AG-CC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 142067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdMnv at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD4	NM_005359.6	c.746_747delAGinsCC	p.Gln249Pro	missense_variant		ENST00000342988.8	NP_005350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD4	ENST00000342988.8	c.746_747delAGinsCC	p.Gln249Pro	missense_variant		5	NM_005359.6	ENSP00000341551.3
ENSG00000267699	ENST00000590722.2	n.*922_*923delAGinsCC		downstream_gene_variant		2		ENSP00000465737.1

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

GnomAD MNV AF: 0.000145 AC: 41 Hom.: 0

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

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: 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. -

Sep 14, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 17, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: 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) -

not specified Benign:1

Jun 16, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SMAD4 c.746_747delinsCC (p.Gln249Pro) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00015 in 251450 control chromosomes. The observed variant frequency is approximately 75.56 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD4 causing Juvenile Polyposis Syndrome phenotype (2e-06). 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). ClinVar contains an entry for this variant (Variation ID: 142067). 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

Dec 03, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: 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. -

Hereditary cancer-predisposing syndrome Benign:1

Dec 23, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Juvenile polyposis syndrome Benign:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.7
Mutation Taster		=1/99	disease causing

Splicing

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

Other links and lift over

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