ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2368A>G (p.Thr790Ala) (rs41286298)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000167808 SCV000075830 benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131470 SCV000186457 likely benign Hereditary cancer-predisposing syndrome 2019-03-05 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Other data supporting benign classification
GeneDx RCV000173843 SCV000209937 likely benign not specified 2017-11-24 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724699 SCV000225002 uncertain significance not provided 2015-04-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131470 SCV000910868 benign Hereditary cancer-predisposing syndrome 2020-02-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000173843 SCV000916717 benign not specified 2018-11-13 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2368A>G (p.Thr790Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 282008 control chromosomes, predominantly within the African subpopulation at a frequency of 0.001 in the gnomAD database. This frequency is about the same as expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.001 vs 0.001), suggesting a benign role for the variant. c.2368A>G has been reported in the literature in several individuals of African and/or African American ancestry affected with Hereditary Breast and Ovarian Cancer. Due to the similarity in the ethnicity between control chromosomes and published reports, these occurrences do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic BRCA1 variants have been reported in the UMD database (c.5324T>G (p.Met1775Arg) in one individual and c.1961dup (p.Tyr655valfsX18) in another), in addition, several co-occurrences with pathogenic BRCA2 variants have also been reported (in the BIC database: c.5946_5946delT (p.Ser1982fsX22) in one individual, and c.8948_8953+5delATTCAGGTAAG in two other individuals; and in LCA internal samples: c.2808delA (p.Lys936fsX24) in one individual and c.5351dupA (p.Asn1784fsX3) in another individual). These multiple co-occurrences strongly support a benign role for the variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as Benign (1x) / Likely benign (2x). Based on the evidence outlined above, the variant was re-classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000724699 SCV001133526 benign not provided 2018-09-27 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286726 SCV001473340 uncertain significance none provided 2020-01-28 criteria provided, single submitter clinical testing The BRCA1 c.2368A>G; p.Thr790Ala variant (rs41286298) is reported in the literature in multiple individuals affected with breast cancer (Cortes 2019, Haffty 2006, Lee 2008, Rummel 2013). However, this variant is also reported to co-occur with pathogenic variants in BRCA1 or BRCA2 by other laboratories in ClinVar (Variant ID: 37465), and is found in the African population with an allele frequency of 0.10% (25/24960 alleles) in the Genome Aggregation Database. The threonine at codon 790 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Although there is evidence to support a benign role for this variant, due to insufficent information, the clinical significance of is uncertain at this time. References: Cortes C et al. Mutational analysis of BRCA1 and BRCA2 genes in women with familial breast cancer from different regions of Colombia. Hered Cancer Clin Pract. 2019 Jul 15;17:20. Haffty BG et al. Racial differences in the incidence of BRCA1 and BRCA2 mutations in a cohort of early onset breast cancer patients: African American compared to white women. J Med Genet. 2006 Feb;43(2):133-7. Lee E et al. Evaluation of unclassified variants in the breast cancer susceptibility genes BRCA1 and BRCA2 using five methods: results from a population-based study of young breast cancer patients. Breast Cancer Res. 2008;10(1):R19. Rummel S et al. Evaluation of BRCA1 mutations in an unselected patient population with triple-negative breast cancer. Breast Cancer Res Treat. 2013 Jan;137(1):119-25.
Sharing Clinical Reports Project (SCRP) RCV000031046 SCV000053640 benign Breast-ovarian cancer, familial 1 2008-11-25 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031046 SCV000144394 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353498 SCV000591383 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Thr790Ala variant was identified in the literature in an African American individual with breast cancer; however, control chromosomes from healthy individuals were not evaluated in this study (Haffty 2005). The variant was also identified in dbSNP (ID: rs41286298) “With unknown allele”, BIC (8X with unknown clinical importance) and UMD (1X as an unclassified variant). Within the UMD record, the variant was noted to co-occur with a known pathogenic mutation in BRCA1 (c.5324T>G (p.Met1775Arg)), increasing the likelihood that the p.Thr790Ala variant may not have clinical significance. In addition, the variant was reported in three of 4460 African American chromosomes (frequency: 0.0007) from the Exome Variant Server ESP Project, increasing the likelihood that may be a low frequency benign variant in certain populations of origin. The p.Thr790 residue is conserved in mammals; however, computational analyses (PolyPhen-2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information 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 unknown significance.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735515 SCV000863653 uncertain significance Breast and/or ovarian cancer 2013-11-04 no assertion criteria provided clinical testing

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