Submissions for variant NM_007294.4(BRCA1):c.1036C>T (p.Pro346Ser)

gnomAD frequency: 0.00032  dbSNP: rs80357015

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000030970	SCV001161569	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00281 (East Asian), derived from gnomAD v2.1.1 non-cancer (2019-05-13).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079175	SCV000075328	benign	Hereditary breast ovarian cancer syndrome	2025-01-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130509	SCV000185378	likely benign	Hereditary cancer-predisposing syndrome	2019-04-03	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	RCV000047315	SCV000209919	likely benign	not specified	2017-05-30	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.
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000047315	SCV000586877	likely benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000030970	SCV000785447	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-08-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130509	SCV000902944	benign	Hereditary cancer-predisposing syndrome	2016-10-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047315	SCV000916714	benign	not specified	2022-01-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1036C>T (p.Pro346Ser) results in a non-conservative amino acid change located in the BRCA1, serine-rich domain of 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 0.00019 in 282696 control chromosomes, predominantly at a frequency of 0.0027 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1036C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Kuo_2012, Sun_2014, Thirthagiri_2008, Flower_2015, Chao_2016, Lai_2017, Chan_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Additionally, multifactorial likelihood analysis classified this variant as neutral (Bouwman_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely benign (n=3) and benign (n=5), including one expert panel (ENIGMA) classified it as benign. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000195311	SCV001133475	benign	not provided	2019-03-12	criteria provided, single submitter	clinical testing
Mendelics	RCV000030970	SCV001140612	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130509	SCV002537990	likely benign	Hereditary cancer-predisposing syndrome	2021-09-15	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002504837	SCV002806667	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-11-04	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000030970	SCV000053561	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-02-13	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000030970	SCV000143987	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2010-09-18	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357043	SCV001552371	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Pro346Ser variant was identified in 3 of 482 proband chromosomes (frequency: 0.006) from Taiwanese and Malaysian individuals or families with breast cancer, early onset breast cancer or a family history of breast and ovarian cancer (Li 1999, Kuo 2012, Thirthagiri 2008). In these studies, the variant was considered a polymorphism, found to co-occur with a pathogenic BRCA2 mutation (exon 3: 490 delCT/STOP 99) in one proband and linkage was not established in another. The variant was also identified in dbSNP (ID: rs80357015) “With other allele”, ClinVar (classified with conflicting interpretations of pathogenicity; benign by Invitae and SCRP (Sharing Clinical Reports Project); likely benign by Ambry Genetics and GeneDx; and uncertain significance by BIC)), Clinvitae (5X), LOVD 3.0 (2x), UMD-LSDB (2-Likely Neutral), BIC Database (4X, unknown clinical importance, classification pending), and Zhejiang Colon Cancer Database (2x); but was not identified in COGR, Cosmic, MutDB, and ARUP Laboratories databases. The variant was identified in control databases in 49 of 276996 chromosomes at a frequency of 0.0002 in the following population: East Asian in 49 of 18868 chromosomes (freq. 0.0025), increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Pro346 residue is not conserved in mammals and four out of five 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, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250469	SCV002520899	likely benign	Familial cancer of breast		no assertion criteria provided	literature only