Submissions for variant NM_007294.4(BRCA1):c.446A>C (p.Glu149Ala)

gnomAD frequency: 0.00004  dbSNP: rs397507233

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240737	SCV000265873	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Ambry Genetics	RCV000219296	SCV000274232	benign	Hereditary cancer-predisposing syndrome	2020-07-16	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458634	SCV000549301	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000479398	SCV000570422	uncertain significance	not provided	2022-06-03	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional study demonstrates no significant difference compared to wild type in a homologous directed repair assay (Lu 2015); Also known as 565A>C; This variant is associated with the following publications: (PMID: 29805665, 27257965, 22116506, 20215511, 30702160, 31825140, 35116780, 32467295, 32548945, 26689913)
Fulgent Genetics, Fulgent Genetics	RCV000764128	SCV000895101	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000219296	SCV000910906	likely benign	Hereditary cancer-predisposing syndrome	2016-04-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000479398	SCV002047334	likely benign	not provided	2020-12-26	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267803	SCV002551057	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002267803	SCV004100168	likely benign	not specified	2023-09-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.446A>C (p.Glu149Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251420 control chromosomes, predominantly at a frequency of 0.0006 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (5.2e-05 vs 0.001), allowing no conclusion about variant significance. c.446A>C has been reported in the literature in individuals affected with early-onset breast cancer, colorectal cancer with suspected Lynch syndrome, stomach adenocarcinoma, and thoracic cancer, all without evidence of causality and often reported as VUS or benign (e.g. Lu_2015, Xu_2020, Wei_2018, Shen_2019, Zhong_2016, Tsang_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (e.g. Lu_2015). These results showed no damaging effect of this variant in an HDR assay. The following publications have been ascertained in the context of this evaluation (PMID: 26689913, 35116780, 36964191, 29805665, 32548945, 27257965). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as benign (n=1), likely benign (n=3), or uncertain significance (n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Sharing Clinical Reports Project (SCRP)	RCV000031175	SCV000053775	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2008-09-04	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357250	SCV001552666	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Glu149Ala variant was identified in 2 of 1302 proband chromosomes (frequency: 0.002) from Chinese individuals or families with sporadic breast cancer (Zhong_2016_27257965, Zhang_2012_ 22116506). A functional validation study of BRCA1 missense variants using a HDR assay in triplicate found the variant’s HDR ability was not impaired (not significant) (Lu_2015_26689913). The variant was also identified in dbSNP (ID: rs397507233) “With Uncertain significance allele”, ClinVar (classified as uncertain significance by Laboratory for Molecular Diagnosis of Cancer (West China Hospital, Sichuan University), Ambry Genetics, Inivitae, GeneDx and SCRP), Clinvitae (5x), and UMD-LSDB (4x 3-UV), and was not identified in GeneInsight-COGR, Cosmic, MutDB, LOVD 3.0, BIC Database, ARUP Laboratories or Zhejiang Colon Cancer Database. The variant was identified in control databases in 14 of 277160 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: Other in 1 of 6464 chromosomes (freq: 0.0002), Latino in 1 of 34418 chromosomes (freq: 0.00003) and East Asian in 12 of 18870 chromosomes (freq: 0.0006) while not observed in the African, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Glu149 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of Ala to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000479398	SCV001800200	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000479398	SCV001951789	likely benign	not provided		no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000031175	SCV004228315	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-01	no assertion criteria provided	clinical testing	BS1(Strong)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
PreventionGenetics, part of Exact Sciences	RCV004758612	SCV005355800	likely benign	BRCA1-related disorder	2024-06-14	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).