Submissions for variant NM_003072.5(SMARCA4):c.2656A>G (p.Met886Val)

dbSNP: rs2146416371

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001533127	SCV001748947	likely pathogenic	SMARCA4-related BAFopathy	2021-06-10	criteria provided, single submitter	clinical testing
GeneDx	RCV001577137	SCV001804469	uncertain significance	not provided	2019-05-13	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab	RCV001810073	SCV002056182	uncertain significance	Intellectual disability, autosomal dominant 16	2021-07-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001873782	SCV002260391	uncertain significance	Rhabdoid tumor predisposition syndrome 2	2021-12-02	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 1177366). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 886 of the SMARCA4 protein (p.Met886Val).
Daryl Scott Lab, Baylor College of Medicine	RCV001810073	SCV002515287	likely pathogenic	Intellectual disability, autosomal dominant 16	2022-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003161070	SCV003864467	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-01-25	criteria provided, single submitter	clinical testing	The p.M886V variant (also known as c.2656A>G), located in coding exon 18 of the SMARCA4 gene, results from an A to G substitution at nucleotide position 2656. The methionine at codon 886 is replaced by valine, an amino acid with highly similar properties. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010). This alteration has been observed in individuals with a personal and/or family history that is consistent with Coffin-Siris syndrome (Levy MA et al. HGG Adv, 2022 Jan;3:100075; Belanger Deloge R et al. Eur J Hum Genet, 2022 Dec; Ambry internal data). In addition, this variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with Coffin-Siris syndrome (personal communication). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) 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 likely pathogenic for Coffin-Siris syndrome; however, the association of this alteration with rhabdoid tumor predisposition syndrome is unknown.