Submissions for variant NM_007294.4(BRCA1):c.3296C>T (p.Pro1099Leu)

gnomAD frequency: 0.00016  dbSNP: rs80357201

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112051	SCV000244337	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-10	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 = 0.0000000000309
Invitae	RCV001084180	SCV000076141	benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000048128	SCV000167290	benign	not specified	2014-01-23	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000112051	SCV000195917	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162544	SCV000212948	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Vantari Genetics	RCV000162544	SCV000267007	likely benign	Hereditary cancer-predisposing syndrome	2016-01-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000112051	SCV000488317	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-02-25	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000048128	SCV000538448	uncertain significance	not specified	2016-06-16	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multiple papers descrive as non-pathogenic; ClinVar: 4 B/LB
Color Diagnostics, LLC DBA Color Health	RCV000162544	SCV000683096	likely benign	Hereditary cancer-predisposing syndrome	2015-02-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034740	SCV000699016	benign	not provided	2016-03-25	criteria provided, single submitter	clinical testing	Variant summary: The variant c.3296C>T affects a conserved nucleotide, leading to amino acid change from Pro to Leu. 3/4 in-silico tools predict this variant to be damaging, however they are not definite. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.0.00026 (32/122380 chromosomes), which does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA1 (0.001). However, the frequency data should still suggest that this variant is likely to be a rare polymorphism. In reputable databases (BIC and UMD), the variant has been reported to co-occur with multiple deleterious pathogenic variants in BRCA1 (p.Glu1060Ter, c.2376_2376delG and c.798_799delTT) as well as in BRCA2 (c.4277delC and c.5353delA). In addition, the variant is also known to be present with a deleterious BRCA1 variant p.Glu1060Ter (Judkins_2005), a definite evidence for benign outcome. Multifactorial probability model studies also show the variant to have a very low probability of being deleterious. Multiple clinical laboratories, reputable databases, and literature classify this variant as benign/polymorphism. Taken all together, this variant has been classified as Benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000112051	SCV000743406	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-09	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000112051	SCV000744638	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000112051	SCV001287306	likely benign	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798071	SCV002043439	likely benign	Breast and/or ovarian cancer	2020-11-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034740	SCV002048625	benign	not provided	2023-08-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162544	SCV002538196	likely benign	Hereditary cancer-predisposing syndrome	2021-03-31	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV000112051	SCV002556881	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2021-08-23	criteria provided, single submitter	clinical testing	The BRCA1 c.3296C>T variant is classified as Benign (BS1, BP6)
Fulgent Genetics, Fulgent Genetics	RCV002496523	SCV002811403	benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-10-21	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000048128	SCV004026780	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952398	SCV004768132	benign	BRCA1-related condition	2020-03-27	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034740	SCV000043168	probably not pathogenic	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Likely benign.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112051	SCV000144704	benign	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	RCV000034740	SCV001551035	likely benign	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.Pro1099Leu variant was identified in 22 of 114568 proband chromosomes (frequency: 0.0002) from individuals or families with breast or ovarian cancer (Judkins 2005, Simard 2007, Borg 2010). The variant was also identified in the following databases: dbSNP (ID: rs80357201) as "With other allele ", ClinVar (classified as benign by Invitae, Ambry Genetics, GeneDx and 7 other submitters; as likely benign by three submitters; as uncertain significance by one submitter), MutDB, LOVD 3.0 (10x), UMD-LSDB (19x as neutral), BIC Database (23x with no clinical importance), and in ARUP Laboratories (not pathogenic or of no clinical significance). In UMD the variant was identified with a co-occurring pathogenic BRCA2 variant (c.4277delC, p.Thr1426Asns*22 and c.5353delA, p.Thr1785Leufs*6), increasing the likelihood that the p.Pro1099Leu variant does not have clinical significance. The variant was not identified in COGR, Cosmic, or Zhejiang University databases. The variant was identified in control databases in 87 of 276300 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 3 of 6452 chromosomes (freq: 0.0005), Latino in 17 of 34400 chromosomes (freq: 0.0005), European in 30 of 126188 chromosomes (freq: 0.0002), East Asian in 1 of 18866 chromosomes (freq: 0.00005), Finnish in 14 of 25458 chromosomes (freq: 0.0006), and South Asian in 22 of 30778 chromosomes (freq: 0.0007); it was not observed in the African or Ashkenazi Jewish populations. The p.Pro1099 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. A few cancer research articles identified this variant in trans with known deleterious mutations (917delTT and E1060X) in clinical specimens, increasing the likelihood that the p.Pro1099Leu variant does not have clinical significance (Judkins 2005, Judkins 2005, Spurdle 2008). In addition, the variant was classified as neutral with probability of being deleterious is 3.09√ó10-11 by a computational model for BRCA1 and BRCA2 variants that factored in data on segregation, co-occurrence, personal and family histories, and pathology (Lindor 2012). 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000048128	SCV001905957	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000048128	SCV001956621	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000112051	SCV004244057	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing