Submissions for variant NM_000059.4(BRCA2):c.449A>G (p.His150Arg)

gnomAD frequency: 0.00001  dbSNP: rs397507722

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000044425	SCV000072438	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 150 of the BRCA2 protein (p.His150Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 15876480, 35264596). This variant is also known as 677A>G. ClinVar contains an entry for this variant (Variation ID: 51657). 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 BRCA2 protein function with a negative predictive value of 95%. 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	RCV000130685	SCV000185572	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-31	criteria provided, single submitter	clinical testing	The p.H150R variant (also known as c.449A>G), located in coding exon 4 of the BRCA2 gene, results from an A to G substitution at nucleotide position 449. The histidine at codon 150 is replaced by arginine, an amino acid with highly similar properties. This alteration was observed in 1 of 92 breast and/or ovarian cancer families from Spain (Salazar R et al. Cancer Lett. 2006 Feb 20;233(1):172-7). This alteration was also detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genetic Services Laboratory, University of Chicago	RCV000499599	SCV000593741	uncertain significance	not specified	2016-09-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130685	SCV000688880	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-17	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 150 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two related individuals affected with breast cancer and an individual with a family history of pancreatic cancer (PMID: 15876480, 35714671). This variant has not been identified 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.
Counsyl	RCV000663195	SCV000786370	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-04-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000044425	SCV000838732	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759616	SCV000889049	uncertain significance	not provided	2018-08-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000663195	SCV001138960	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000759616	SCV001830571	uncertain significance	not provided	2023-03-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 677A>G; Observed in individuals with a personal or family history including breast cancer and other cancers (Salazar et al., 2006; Li et al., 2020; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 35264596, 35743882, 32377563, 29884841, 31853058, 15876480)