Submissions for variant NM_000059.4(BRCA2):c.3310A>C (p.Thr1104Pro)

gnomAD frequency: 0.00002  dbSNP: rs80358577

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044176	SCV000072189	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-24	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1104 of the BRCA2 protein (p.Thr1104Pro). This variant is present in population databases (rs80358577, gnomAD 0.003%). This missense change has been observed in individual(s) with a personal or family history of breast cancer (PMID: 22977638, 31851867). This variant is also known as 3538A>C. ClinVar contains an entry for this variant (Variation ID: 51448). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000163592	SCV000214154	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-10	criteria provided, single submitter	clinical testing	The p.T1104P variant (also known as c.3310A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 3310. The threonine at codon 1104 is replaced by proline, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758881	SCV000887787	uncertain significance	not provided	2024-04-17	criteria provided, single submitter	clinical testing	The BRCA2 c.3310A>C (p.Thr1104Pro) variant has been reported in the published literature in individuals with a personal or family history of breast cancer (PMIDs: 36605468 (2023), 32658311 (2021), 31851867 (2020)), and also observed in reportedly healthy individuals (PMIDs: 32658311 (2021), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). This variant has been shown to have neutral effects on DNA repair-associated cell survival in a drug sensitivity assay (PMID: 37922907 (2023)), and described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000037 (4/108720 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000163592	SCV000906661	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-18	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with proline at codon 1104 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two individuals affected with breast or ovarian cancer and in two unaffected individuals (DOI: 10.5603/OCP.2020.0026, 10.1515/tjb-2019-0424, PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008063, 36605468). This variant has been identified in 4/235948 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781094	SCV000918914	uncertain significance	not specified	2022-03-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3310A>C (p.Thr1104Pro) results in a non-conservative amino acid change located in the outside of any known functional domain or repeat of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 235988 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3310A>C has been reported in the literature in at-least one individual with breast cancer in whom a co-occurrence with another pathogenic variant was reported (BRCA1 c.5289delG, p.Leu1764fsX1), providing supporting evidence for a benign role (example, DeSilva_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. In addition, all patients with c.3310A>C, reported in BIC (n=4) and UMD (n=3) also carry another VUS, BRCA2 c.3503T>A (M1168K), suggesting an "in cis" phase for these two variants. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (example, Brough_2012). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000758881	SCV001473489	uncertain significance	not provided	2019-09-12	criteria provided, single submitter	clinical testing	The BRCA2 c.3310A>C; p.Thr1104Pro variant (rs80358577), also known as 3538A>C, is reported in the literature in at least one individual with a family history of breast cancer (DE Silva 2011). A different variant at this codon (c.3311C>G; p.Thr1104Arg) has been reported in an individual with ovarian cancer (Santonocito 2017). The p.Thr1104Pro variant is reported in ClinVar (Variation ID: 51448), and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 1104 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, functional analyses of the variant protein show no change in binding to the APRIN protein (Brough 2012). Due to limited information, the clinical significance of the p.Thr1104Pro variant is uncertain at this time. References: Brough R et al. APRIN is a cell cycle specific BRCA2-interacting protein required for genome integrity and a predictor of outcome after chemotherapy in breast cancer. EMBO J. 2012 Mar 7;31(5):1160-76. DE Silva S et al. Novel sequence variants and common recurrent polymorphisms of BRCA2 in Sri Lankan breast cancer patients and a family with BRCA1 mutations. Exp Ther Med. 2011 Nov;2(6):1163-1170. Santonocito C et al. Identification of twenty-nine novel germline unclassified variants of BRCA1 and BRCA2 genes in 1400 Italian individuals. Breast. 2017 Dec;36:74-78.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000163592	SCV003851847	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000044176	SCV004167631	likely benign	Hereditary breast ovarian cancer syndrome	2023-10-19	criteria provided, single submitter	curation	Cold spot variant outside of functional domains (ClinGen ENIGMA BRCA1/2 rules) in silico prediction benign (BayesDel no AF-0.0862), splice AI no impact (0.0); BP1_strong. According to the ACMG standard criteria we chose this criterium: BP1 (strong benign): Cold spot variant outside of functional domains (ClinGen ENIGMA BRCA1/2 rules) in silico prediction benign (BayesDel no AF-0.0862), splice AI no impact (0.0); BP1_strong
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000781094	SCV004242949	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004803157	SCV004845143	uncertain significance	BRCA2-related cancer predisposition	2024-03-28	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with proline at codon 1104 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 1 individual affected with bilateral breast cancer, 1 individual affected with breast or ovarian cancer, and 2 unaffected individuals (DOI: 10.5603/OCP.2020.0026, 10.1515/tjb-2019-0424, PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008063). This variant has been identified in 4/235948 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP)	RCV000083097	SCV000115171	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083097	SCV000146212	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing