Submissions for variant NM_007294.4(BRCA1):c.5585A>T (p.His1862Leu)

gnomAD frequency: 0.00001  dbSNP: rs80357183

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000049059	SCV000077072	benign	Hereditary breast ovarian cancer syndrome	2024-12-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000774923	SCV000908971	likely benign	Hereditary cancer-predisposing syndrome	2023-11-16	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237433	SCV002009418	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000774923	SCV002654144	likely benign	Hereditary cancer-predisposing syndrome	2020-09-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
MGZ Medical Genetics Center	RCV003607227	SCV004543883	benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR, BS3, BP5_MOD, PM2_SUP
All of Us Research Program, National Institutes of Health	RCV000112707	SCV004817522	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with leucine at codon 1862 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported that this variant does not impact BRCA1 function in homology-directed repair and cisplatin and olaparib sensitivity assays in Brca1-deficient mouse embryonic stem cells (PMID: 32546644). A multifactorial analysis has reported segregation, tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 0.6141, 0.4 , 1.0673 and 0.6716, respectively (PMID: 31131967). This variant has been identified in 1/250882 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.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112707	SCV000145583	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356964	SCV001552271	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.His1862Leu variant was identified in the literature in a study that showed the variant was able to support growth of Brca1–null murine cells in a functional complementation assay (Bouwman 2013). The variant was also identified in dbSNP (ID: rs80357183) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae and BIC), MutDB, LOVD 3.0 (13x), and BIC Database (1x with unknown significance). The variant was not identified in the Cosmic, COGR, UMD-LSDB, ARUP Laboratories, or Zhejiang University databases. The variant was identified in control databases in 1 of 245632 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 111370 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.His1862 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.