Submissions for variant NM_007294.4(BRCA1):c.1703C>T (p.Pro568Leu)

dbSNP: rs80356910

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083171	SCV001161489	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 8.19E-06
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079198	SCV000075577	likely benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131307	SCV000186279	likely benign	Hereditary cancer-predisposing syndrome	2019-01-30	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	RCV000588961	SCV000515690	likely benign	not provided	2019-09-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25777348, 19619314, 19491284, 16931905, 16267036, 16518693, 26207792, 27062684, 31131967, 33087888)
Genetic Services Laboratory, University of Chicago	RCV000443568	SCV000593689	uncertain significance	not specified	2017-03-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131307	SCV000682977	likely benign	Hereditary cancer-predisposing syndrome	2017-03-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000443568	SCV000698882	likely benign	not specified	2024-02-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1703C>T (p.Pro568Leu) 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 8.7e-06 in 1613200 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (8.7e-06 vs 0.001), allowing no conclusion about variant significance. c.1703C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Judkins_2005, Haffty_2009, Palomba_2009, ElSaghir_2015, Lincoln_2015, Azzollini_2016, Santonocito_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported (Azzollini_2016), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 16518693, 15385441, 12531920, 15001988, 19619314, 19491284, 25777348, 26207792, 16931905, 27062684, 32438681). ClinVar contains an entry for this variant (Variation ID: 54329). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588961	SCV000888844	likely benign	not provided	2023-05-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000083171	SCV001287419	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Sema4, Sema4	RCV000131307	SCV002538046	likely benign	Hereditary cancer-predisposing syndrome	2021-06-03	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV000083171	SCV004818296	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-02-24	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000443568	SCV005090359	benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083171	SCV000115245	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083171	SCV000144161	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000083171	SCV000591348	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing	The BRCA1 p.Pro568Leu variant was identified in the literature in at least two individuals or families with early onset or hereditary breast cancer (Haffty 2009, Judkins 2005); however control chromosomes from healthy individuals were not assessed in these studies, thus the prevalence of the variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs80356910) “With uncertain significance allele”, the BIC database (8X with unknown clinical importance), LOVD, and UMD (1X as a class 3-UV variant). The variant was classified as a benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports) along with submission by Invitae and Ambry stating unknown significance. The p.Pro568 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. In silico studies using evolutionary conservation analysis predict this variant to have no effect on the protein (Fleming 2003) or were inconclusive (Burk-Herrick 2005). In silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. However, it should be noted that all of the above in silico predictions are not predictive enough to rule out pathogenicity. 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 predicted benign.