chr18-51058134-C-T
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2
The NM_005359.6(SMAD4):c.677C>T(p.Ala226Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000644 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005359.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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SMAD4 | NM_005359.6 | c.677C>T | p.Ala226Val | missense_variant | Exon 6 of 12 | ENST00000342988.8 | NP_005350.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMAD4 | ENST00000342988.8 | c.677C>T | p.Ala226Val | missense_variant | Exon 6 of 12 | 5 | NM_005359.6 | ENSP00000341551.3 | ||
ENSG00000267699 | ENST00000590722.2 | n.*853C>T | non_coding_transcript_exon_variant | Exon 9 of 9 | 2 | ENSP00000465737.1 | ||||
ENSG00000267699 | ENST00000590722.2 | n.*853C>T | 3_prime_UTR_variant | Exon 9 of 9 | 2 | ENSP00000465737.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152162Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000836 AC: 21AN: 251344Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135848
GnomAD4 exome AF: 0.0000691 AC: 101AN: 1461806Hom.: 0 Cov.: 33 AF XY: 0.0000468 AC XY: 34AN XY: 727204
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152280Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74472
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
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not provided Uncertain:1Benign:2
Observed in individuals with a personal history of colon cancer and other cancers, but has not been reported in association with heritable disorders of connective tissue to our knowledge (PMID: 28528518, 27978560, 28135145); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28528518, 27978560, 28135145, 18823382, 22992590, 15235019, 37937776) -
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SMAD4: BP4 -
SMAD4-related disorder Uncertain:1
The SMAD4 c.677C>T variant is predicted to result in the amino acid substitution p.Ala226Val. This variant has been reported as a germline variant in two individuals with colorectal cancer (Table A4. Yurgelun et al. 2017. PubMed ID: 28135145; Table e2. Pearlman et al. 2017. PubMed ID: 27978560) and in an individual with breast cancer who was reported to have a pathogenic variant in BRCA2 (Cock-Rada et al. 2018. PubMed ID: 28528518). This variant has been reported in the gnomAD public population database in 21 of ~251,000 alleles and is listed in ClinVar with conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/182869/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Carcinoma of pancreas;C0796081:Myhre syndrome;C1832942:Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome;C1868081:Generalized juvenile polyposis/juvenile polyposis coli Uncertain:1
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Generalized juvenile polyposis/juvenile polyposis coli Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not specified Benign:1
Variant summary: SMAD4 c.677C>T (p.Ala226Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251344 control chromosomes. The observed variant frequency is approximately 41.78 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD4 causing Juvenile Polyposis Syndrome phenotype (2e-06). c.677C>T has been reported in the literature in one individuals affected with colorectal cancer, without strong evidence for causality (Yurgelun_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Juvenile Polyposis Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication hasbeen ascertained in the context of this evaluation (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 182869). Based on the evidence outlined above, the variant was classified as likely benign. -
Myhre syndrome Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1
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. -
Juvenile polyposis syndrome Benign:1
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Myhre syndrome;C1832942:Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Other:1
Variant interpreted as Likely benign and reported on 01-28-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at