Submissions for variant NM_007294.4(BRCA1):c.5425G>T (p.Val1809Phe)

dbSNP: rs28897698

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235944	SCV000293325	likely pathogenic	not provided	2021-10-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: decreased transcriptional activity, peptide binding activity and specificity (Williams 2004, Phelan 2005, Fernandes 2019, Drikos 2021); Observed in individuals with breast and ovarian cancer, segregating with disease in one family (Phelan 2005, Thomassen 2008, Fostira 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Not observed in large population cohorts (Lek et al., 2016); Also known as 5544G>T; This variant is associated with the following publications: (PMID: 16528612, 31131967, 15689452, 17305420, 19452558, 21447777, 15172985, 20516115, 14534301, 15133503, 18465347, 15385441, 20167696, 17719744, 28781887, 30765603, 31300551, 32123317, 32546644, 34083286)
Color Diagnostics, LLC DBA Color Health	RCV001185950	SCV001352265	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-07-31	criteria provided, single submitter	clinical testing	This missense variant replaces valine with phenylalanine at codon 1809 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 in homology-directed repair, transcription activation and cisplatin and olaparib sensitivity assays and may compromise protein stability, protein localization, and protein-protein interaction (PMID: 14534301, 15133503, 15689452, 16528612, 19452558, 20516115, 28781887, 32546644, 34083286). This variant has been observed in multiple individuals affected with breast cancer from at least three unrelated families (PMID: 15689452, 18465347, 31300551, 33471991; Leiden Open Variation Database DB-ID BRCA1_000474), including an individual affected with breast and endometrial cancer (PMID: 31300551) and the co-segregation with four affected members of a hereditary breast cancer family (PMID: 15689452). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae	RCV001302952	SCV001492180	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1809 of the BRCA1 protein (p.Val1809Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of breast, ovarian and/or endometrial cancer (PMID: 15689452, 18465347, 31300551). It has also been observed to segregate with disease in related individuals. This variant is also known as 5544G>T. ClinVar contains an entry for this variant (Variation ID: 55573). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA1 protein function. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 15689452, 19452558, 20516115, 28781887, 32546644, 34083286). 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.
Ambry Genetics	RCV001185950	SCV003856685	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	The p.V1809F variant (also known as c.5425G>T), located in coding exon 21 of the BRCA1 gene, results from a G to T substitution at nucleotide position 5425. The valine at codon 1809 is replaced by phenylalanine, an amino acid with highly similar properties. This variant has been identified in breast cancer cohorts and has been shown to segregate with disease in one family (Phelan CM et al. J Med Genet, 2005 Feb;42:138-46; Thomassen M et al. Acta Oncol, 2008;47:772-7; Fostira F et al. J Med Genet 2020 Jan;57(1):53-61). Protein functional studies have demonstrated this variant to have a deleterious impact on function (Bouwman P et al. Clin Cancer Res, 2020 Sep;26:4559-4568; Woods NT et al. NPJ Genom Med, 2016 Mar;1:16001; Fernandes VC et al. J Biol Chem, 2019 Apr;294:5980-5992; Lee MS et al. Cancer Res, 2010 Jun;70:4880-90; Drikos I et al. Anticancer Res, 2021 Jun;41:2953-2962). This alteration was inconclusive in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence, tumor pathology and case-control data (Parsons MT et al. Hum Mutat 2019 Sep;40(9):1557-1578). Of note, this alteration is also referred to as c.5544G>T in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112651	SCV000145509	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing