ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.446A>C (p.Glu149Ala) (rs397507233)

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Total submissions: 8
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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 In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);No disease association in small case-control study;Subpopulation frequency in support of benign classification
Invitae RCV000458634 SCV000549301 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000479398 SCV000570422 uncertain significance not provided 2018-09-25 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.446A>C at the cDNA level, p.Glu149Ala (E149A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAA>GCA). Using alternate nomenclature, this variant would be defined as BRCA1 565A>C. This variant was observed in several individuals with breast cancer and in one individual with gastric cancer (Zhang 2012, Lu 2015, Zhong 2016, Wei 2018). Functional analysis of this variant showed no significant difference as compared to wild type in a homologous directed repair assay (Lu 2015). BRCA1 Glu149Ala was observed at an allele frequency of 0.06% (12/18870) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located within a region that binds BRD7 (Harte 2010). Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, predicts that this variant is probably damaging to protein structure and function, and splicing models are uninformative in their assessment as to whether or not the variant is damaging. Based on currently available evidence, it is unclear whether BRCA1 Glu149Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Fulgent Genetics,Fulgent Genetics RCV000764128 SCV000895101 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4; Fanconi anemia, complementation group S 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000219296 SCV000910906 likely benign Hereditary cancer-predisposing syndrome 2016-04-19 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031175 SCV000053775 uncertain significance Breast-ovarian cancer, familial 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.

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