Submissions for variant NM_007294.4(BRCA1):c.3454G>A (p.Asp1152Asn)

gnomAD frequency: 0.00004  dbSNP: rs80357175

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001081256	SCV000076216	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129496	SCV000184268	likely benign	Hereditary cancer-predisposing syndrome	2019-01-03	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.
GeneDx	RCV000589160	SCV000210147	uncertain significance	not provided	2019-04-10	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20104584, 18500671, 15235020, 25948282, 21232165, 26689913, 26580448, 26941049, 21520273, 25682074, 23704879, 15385441)
Department of Pathology and Molecular Medicine, Queen's University	RCV000212174	SCV000588045	uncertain significance	not specified	2017-04-20	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212174	SCV000593681	uncertain significance	not specified	2016-09-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589160	SCV000600334	likely benign	not provided	2023-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212174	SCV000699034	likely benign	not specified	2023-03-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3454G>A (p.Asp1152Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251338 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (4e-05 vs 0.001), allowing no conclusion about variant significance. c.3454G>A has been reported in the literature in individuals affected with breast and/or ovarian cancer without strong evidence for causality (e.g. Hansen_2009, Borg_2010, Stegel_2011, Wong-Brown_2015, Kluska_2015, Zhang_2015, Santonocito_2020, Hauke_2022). Therefore, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with a likely pathogenic variant (BRCA1 c.4485_4675del, p.Ser1496GlyfsX14) has also been reported, providing supporting evidence for a benign role (UMD database). At least two publications report experimental evidence evaluating an impact on protein function (e.g. Lu_2015, Bouwman_2020). The results of these studies showed no damaging effect of this variant on homology directed repair (HDR) activity and no impairment on its ability to complement BRCA1-deficient mouse embryonic stem cells in homologous recombination DNA repair (HRR) using cisplatin and olaparib sensitivity assays and a direct GFP HRR assay. HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. Fourteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=9) or likely benign (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV000589160	SCV000806934	uncertain significance	not provided	2017-08-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129496	SCV000902880	likely benign	Hereditary cancer-predisposing syndrome	2015-04-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000589160	SCV001151331	uncertain significance	not provided	2022-06-01	criteria provided, single submitter	clinical testing	BRCA1: PM2, BP1
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212174	SCV001160216	uncertain significance	not specified	2019-01-09	criteria provided, single submitter	clinical testing	The BRCA1 c.3454G>A; p.Asp1152Asn variant (rs80357175), also known as 3573G>A in traditional nomenclature, is reported in the literature in multiple individuals affected with breast and/or ovarian cancer, as well as one pediatric patient with leukemia (Borg 2010, Kluska 2015, Stegel 2011, Zhang 2015). This variant is reported as uncertain significance by multiple laboratories in ClinVar (Variation ID: 54890), and is found in the non-Finnish European population with an allele frequency of 0.0085% (11/129,078 alleles) in the Genome Aggregation Database. The aspartic acid at codon 1152 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. In vitro functional analyses demonstrate activity similar to wildtype in a homology-directed repair assay (Lu 2015). Due to limited information, the clinical significance of the p.Asp1152Asn variant is uncertain at this time. References: Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. Kluska A et al. New recurrent BRCA1/2 mutations in Polish patients with familial breast/ovarian cancer detected by next generation sequencing. BMC Med Genomics. 2015 May 7;8:19. Lu C et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun. 2015 Dec 22;6:10086. Stegel V et al. The occurrence of germline BRCA1 and BRCA2 sequence alterations in Slovenian population. BMC Med Genet. 2011 Jan 14;12:9. Zhang J et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med. 2015 Dec 10;373(24):2336-2346.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196675	SCV001367306	uncertain significance	Familial cancer of breast	2019-09-16	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,BP1.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000112100	SCV001440658	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-01-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129496	SCV002538211	likely benign	Hereditary cancer-predisposing syndrome	2020-12-11	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129496	SCV003846905	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).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112100	SCV000144768	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000112100	SCV000297600	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2010-01-14	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353524	SCV000591448	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Asp1152Asn variant was identified in 1 of 1042 proband chromosomes (frequency: 0.001) from Slovenian individuals or families with breast and/or ovarian cancers, and was not identified in 80 control chromosomes from healthy individuals (Stegel 2011). The variant was identified by our laboratory in 2 individuals with breast cancer. The variant was also identified in dbSNP (ID: rrs80357175 “With Uncertain significance allele”. The variant was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 2 of 121314 chromosomes (frequency: 0.00001649) or 2 of 66712 European (Non-Finnish) alleles and was not found in populations of South Asians, East Asian, African, Latino, European (Finnish) and other individuals. The p.Asp1152Asn variant was identified in the Clinvar database and was classified as a variant of uncertain significance by Ambry Genetics, GeneDx and BIC; Invitae did not provide a classification. The BRCA Share UMD database identified the variant 3X and classified it as unknown; the variant was identified with a co-occurring BRCA1 pathogenic variant (c.4485_4675del, p.Ser1496GlyfsX14), increasing the likelihood that the p.Asp1152Asn variant does not have clinical significance. BIC database identified the variant 3X with unknown clinical importance. The p.Asp1152 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. In addition, evolutionary conservation analysis predicts the variant as neutral (Abkevich 2004). 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.
MVZ Praenatalmedizin und Genetik Nuernberg	RCV000112100	SCV000777893	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2018-05-01	no assertion criteria provided	clinical testing	This rare variant (gnomAD) was found multiple times in databases and literature with uncertain significance. In silico analyses show contradictory results. Therefore we rate this variant as Variant of unknown significance (VUS). Interestingly we found this variant in a patient who harbored also a pathogenic BRCA2-variant (NM_000059.3|c.5238dupT|het)
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000112100	SCV004171672	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-24	no assertion criteria provided	clinical testing