Submissions for variant NM_000059.4(BRCA2):c.5487G>T (p.Leu1829Phe)

gnomAD frequency: 0.00001  dbSNP: rs779967765

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240748	SCV000265945	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456588	SCV000549585	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-02	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1829 of the BRCA2 protein (p.Leu1829Phe). This variant is present in population databases (rs779967765, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 27257965, 32885271, 35300142, 35918668). ClinVar contains an entry for this variant (Variation ID: 224465). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
GeneDx	RCV000482177	SCV000565920	uncertain significance	not provided	2015-03-10	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.5487G>T at the cDNA level, p.Leu1829Phe (L1829F) at the protein level, and results in the change of a Leucine to a Phenylalanine (TTG>TTT). Using alternate nomenclature, this variant would be defined as BRCA2 5715G>T. This variant has not, to our knowledge, been published in the literature as either a germline pathogenic variant or a benign polymorphism. However, this variant has been reported as a somatic variant in a breast tumor (Harismendy 2013). BRCA2 Leu1829Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Leu1829Phe occurs at a position that is not conserved across species and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Leu1829Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000574898	SCV000673106	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-30	criteria provided, single submitter	clinical testing	The p.L1829F variant (also known as c.5487G>T), located in coding exon 10 of the BRCA2 gene, results from a G to T substitution at nucleotide position 5487. The leucine at codon 1829 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Zhong X et al. PLoS ONE, 2016 Jun;11:e0156789; Luo Y et al. Int J Gen Med, 2022 Mar;15:2773-2786; Zhang Y et al. BMC Cancer, 2022 Aug;22:842). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000574898	SCV000683707	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-11	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 1829 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 individuals affected with breast, pancreatic, or ovarian cancer (PMID: 27257965, 32885271, 33471991, 35300142). In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 1/53461 unaffected controls, showing inconclusive association with disease (OR=1.768 (95%CI 0.16 to 19.503); p-value=1; Leiden Open Variation Database DB-ID BRCA2_003813) (PMID: 33471991). This variant has been identified in 4/282356 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	RCV002509304	SCV002819807	uncertain significance	not specified	2022-12-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5487G>T (p.Leu1829Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250962 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5487G>T has been reported in the literature as a VUS in at-least one individual affected with breast cancer (example, Zhong_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000574898	SCV003848851	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).
MGZ Medical Genetics Center	RCV002250598	SCV004543899	likely benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR, BS1_SUP
All of Us Research Program, National Institutes of Health	RCV004804853	SCV004846584	uncertain significance	BRCA2-related cancer predisposition	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 1829 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 individuals affected with breast, pancreatic, or ovarian cancer (PMID: 27257965, 32885271, 33471991, 35300142). In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 1/53461 unaffected controls, showing inconclusive association with disease (OR=1.768 (95%CI 0.16 to 19.503); p-value=1; Leiden Open Variation Database DB-ID BRCA2_003813) (PMID: 33471991). This variant has been identified in 4/282356 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356089	SCV001551153	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The BRCA2 p.Leu1829Phe variant was identified in 2 of 1090 proband chromosomes (frequency: 0.002) from individuals with breast cancer and tumour DNA samples (Zhong 2016, Harismendy 2013). The variant was identified in dbSNP (rs779967765) as “with likely benign, uncertain significance allele”, ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx, Color and Sichuan University) and LOVD 3.0 (observed 2x). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 4 of 282,356 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 4 of 19,950 chromosomes (freq: 0.0002); it was not observed in the African, Latino, Ashkenazi Jewish, Finnish, European, Other or South Asian populations. The p.Leu1829 residue is not conserved in mammals and 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250598	SCV002520803	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only