Submissions for variant NM_003072.5(SMARCA4):c.403C>G (p.Pro135Ala)

gnomAD frequency: 0.00012  dbSNP: rs150949949

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227247	SCV000286066	likely benign	Rhabdoid tumor predisposition syndrome 2	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000571456	SCV000663934	likely benign	Hereditary cancer-predisposing syndrome	2018-12-04	criteria provided, single submitter	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.
GeneDx	RCV001356659	SCV002319048	uncertain significance	not provided	2022-03-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously reported as pathogenic or benign in association with neurodevelopmental disorders to our knowledge; This variant is associated with the following publications: (PMID: 33558524)
Sema4, Sema4	RCV000571456	SCV002532942	benign	Hereditary cancer-predisposing syndrome	2020-12-29	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001356659	SCV004220441	uncertain significance	not provided	2023-09-21	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with breast cancer and in an individual with ovarian cancer (PMIDs: 33558524 (2021) and 37460928 (2023)). The frequency of this variant in the general population, 0.00028 (10/35414 chromosomes in Latino/Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Center of Medical Genetics and Primary Health Care	RCV001005023	SCV000987283	uncertain significance	bilateral breast cancer	2020-04-08	no assertion criteria provided	research	ACMG Guidelines 2015 criteria PP4 Pathogenic Supporting: Female patient was diagnosed with bilateral breast cancer at the age of 40 y.o. BS1 Benign Strong: GnomAD exomes allele frequency = 0.000193 > 0.0001 derived from the 1,851 clinically reported variants: 81 PATH, 952 VUS and 818 BEN. BS2 Benign Strong: Observed in healthy adults: GnomAD exomes allele count = 48 > 5 threshold for dominant gene SMARCA4. BP4 Benign Supporting: 7 benign predictions from DANN, DEOGEN2, EIGEN, MVP, MutationAssessor, PrimateAI and REVEL vs 6 pathogenic predictions from FATHMM-MKL, M-CAP, MutationTaster, SIFT, PolyPhen-2, Align-GVGD and the position is not conserved. This variant has not been reported in the literature in individuals with SMARCA4-related disease. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356659	SCV001551889	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SMARCA4 p.P135A variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs150949949) and ClinVar (classified as uncertain significance by Invitae and Ambry Genetics). The variant was identified in control databases in 44 of 265648 chromosomes at a frequency of 0.0001656 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 10 of 35086 chromosomes (freq: 0.000285), European (non-Finnish) in 28 of 115610 chromosomes (freq: 0.000242), South Asian in 3 of 30526 chromosomes (freq: 0.000098), European (Finnish) in 2 of 25092 chromosomes (freq: 0.00008) and African in 1 of 23562 chromosomes (freq: 0.000042), but was not observed in the Ashkenazi Jewish, East Asian or Other populations. The p.P135 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.
PreventionGenetics, part of Exact Sciences	RCV003967624	SCV004780978	likely benign	SMARCA4-related disorder	2023-07-20	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).