Submissions for variant NM_007294.4(BRCA1):c.716A>T (p.His239Leu)

dbSNP: rs80357396

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215014	SCV000275267	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-11	criteria provided, single submitter	clinical testing	The p.H239L variant (also known as c.716A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 716. The histidine at codon 239 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in an individual with breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is not well 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.
Invitae	RCV000226910	SCV000289840	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 239 of the BRCA1 protein (p.His239Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 231422). 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 BRCA1 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.
Counsyl	RCV000410574	SCV000489421	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-10-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000485971	SCV000567570	uncertain significance	not provided	2017-12-12	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.716A>T at the cDNA level, p.His239Leu (H239L) at the protein level, and results in the change of a Histidine to a Leucine (CAT>CTT). Using alternate nomenclature, this variant would be defined as BRCA1 835A>T. This variant has been reported in at least one individual with breast cancer (Tung 2015). BRCA1 His239Leu was not observed in large population cohorts (Lek 2016). Since Histidine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 His239Leu is located in a region known to interact with multiple proteins (Paul 2014). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 His239Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000215014	SCV000688660	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-15	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with leucine at codon 239 of the BRCA1 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 individuals affected with breast cancer in the literature (PMID: 25186627, 27478808). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485971	SCV001133644	uncertain significance	not provided	2021-03-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000410574	SCV001284086	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000215014	SCV003847994	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health	RCV000410574	SCV004818419	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with leucine at codon 239 of the BRCA1 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 individuals affected with breast cancer in the literature (PMID: 25186627, 27478808). 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.