ClinVar Miner

Submissions for variant NM_003072.5(SMARCA4):c.2838del (p.Phe947fs)

dbSNP: rs2146423140
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001903188 SCV002161076 pathogenic Rhabdoid tumor predisposition syndrome 2 2021-04-16 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with SMARCA4-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Phe947Leufs*3) in the SMARCA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMARCA4 are known to be pathogenic (PMID: 24658001, 24658002).
Ambry Genetics RCV002440990 SCV002752648 pathogenic Hereditary cancer-predisposing syndrome 2021-01-12 criteria provided, single submitter clinical testing The c.2838delC pathogenic mutation, located in coding exon 18 of the SMARCA4 gene, results from a deletion of one nucleotide at nucleotide position 2838, causing a translational frameshift with a predicted alternate stop codon (p.F947Lfs*3). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) (Ambry internal data). This alteration has also been reported as a somatic mutation in SCCOHT and in uterine sarcoma tumors (Witkowski L et al. Nat Genet, 2014 May;46:438-43; Lin DI et al. Mod Pathol, 2019 11;32:1675-1687). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Loss-of-function variants in SMARCA4 are known to cause rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT); however, such associations with neurodevelopmental disorders are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). Based on the supporting evidence, this alteration is pathogenic for rhabdoid tumor predisposition syndrome; however, the association of this alteration with Coffin-Siris syndrome is unlikely.

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