Submissions for variant NM_032043.3(BRIP1):c.820A>G (p.Thr274Ala)

gnomAD frequency: 0.00002  dbSNP: rs62620988

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130310	SCV000185160	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-22	criteria provided, single submitter	clinical testing	The p.T274A variant (also known as c.820A>G), located in coding exon 6 of the BRIP1 gene, results from an A to G substitution at nucleotide position 820. The threonine at codon 274 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8). In one study, this alteration was observed in 8/36687 control samples and absent in 706 cases with ovarian cancer and 6341 cases with breast cancer (Weber-Lassalle N et al. Breast Cancer Res., 2018 01;20:7).This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000588437	SCV000567806	uncertain significance	not provided	2024-07-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer, but also in unaffected controls (PMID: 26976419, 29368626, 33471991); This variant is associated with the following publications: (PMID: 29368626, 26976419, 33471991)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000527670	SCV000633716	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 274 of the BRIP1 protein (p.Thr274Ala). This variant is present in population databases (rs62620988, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 141694). 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) performed at Invitae indicates that this missense variant is not expected to disrupt BRIP1 protein function with a negative predictive value of 80%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000130310	SCV000684305	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 274 of the BRIP1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26976419). This variant has also been identified in 10/282442 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222404	SCV000699735	uncertain significance	not specified	2022-03-03	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.820A>G (p.Thr274Ala) results in a non-conservative amino acid change located in the DEAD2 domain (IPR010614) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.5e-05 in 282442 control chromosomes, predominantly at a frequency of 7.8e-05 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is somewhat higher than the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Hereditary Breast and Ovarian Cancer Syndrome phenotype (6.3e-05), suggesting that the variant might be a benign polymorphism. The variant, c.820A>G, has been reported in the literature in individuals affected with breast cancer (Tung_2016, Dorling_2021), but was also found in controls (Dorling_2021). In addition, one of these reported individuals also carried another pathogenic variant (BRCA2 c.7618-1G>A, Tung_2016), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014, and all of them classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Illumina Laboratory Services, Illumina	RCV001125838	SCV001284960	uncertain significance	Fanconi anemia complementation group J	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Sema4, Sema4	RCV000130310	SCV002529238	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-18	criteria provided, single submitter	curation
Baylor Genetics	RCV004567109	SCV005059919	uncertain significance	Familial cancer of breast	2023-12-27	criteria provided, single submitter	clinical testing