Submissions for variant NM_032043.3(BRIP1):c.2464T>C (p.Tyr822His)

gnomAD frequency: 0.00001  dbSNP: rs760887592

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196234	SCV000255153	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 822 of the BRIP1 protein (p.Tyr822His). This variant is present in population databases (rs760887592, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 31822495). ClinVar contains an entry for this variant (Variation ID: 216788). 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 BRIP1 protein function. Experimental studies have shown that this missense change affects BRIP1 function (PMID: 31822495). 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	RCV000574768	SCV000666222	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-21	criteria provided, single submitter	clinical testing	The p.Y822H variant (also known as c.2464T>C), located in coding exon 16 of the BRIP1 gene, results from a T to C substitution at nucleotide position 2464. The tyrosine at codon 822 is replaced by histidine, an amino acid with similar properties. This alteration was detected in 1/101,759 breast cancer cases and 0/15,587 ovarian cancer cases, and in an inter-strand cross link damage survival assay, this alteration was found to be functionally hypomorphic (Moyer CL et al. Cancer Res. 2020 Feb;80:857-867). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000574768	SCV000909764	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-01	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 822 of the BRIP1 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). A functional study has shown that the variant protein partially rescued cells in response to DNA damage in a cell viability assay (PMID: 31822495). This variant has been reported in an individual affected with breast cancer (PMID: 31822495). This variant has been identified in 1/250042 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.
Baylor Genetics	RCV003462342	SCV004217037	uncertain significance	Familial cancer of breast	2023-07-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526640	SCV005039132	uncertain significance	not specified	2024-03-25	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.2464T>C (p.Tyr822His) results in a conservative amino acid change located in the ATP-dependent helicase, C-terminal domain (IPR006555) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250042 control chromosomes (gnomAD). c.2464T>C has been reported in the literature in individuals affected with Breast Cancer without strong evidence of causality (Weber-Lassalle_2018, Moyer_2020). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant does not fully rescue interstrand cross-link activity and was considered hypomorphic (Moyer_2020). The following publications have been ascertained in the context of this evaluation (PMID: 31822495, 29368626). ClinVar contains an entry for this variant (Variation ID: 216788). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.