Submissions for variant NM_007294.4(BRCA1):c.4843G>A (p.Ala1615Thr)

gnomAD frequency: 0.00001  dbSNP: rs80356987

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048677	SCV000076690	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1615 of the BRCA1 protein (p.Ala1615Thr). This variant is present in population databases (rs80356987, gnomAD 0.0009%). This missense change has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 12142080, 17453335, 22752604, 24884479, 25896959, 27062684, 35023674). This variant is also known as 4962G>A. ClinVar contains an entry for this variant (Variation ID: 55302). 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 BRCA1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 28781887, 30765603, 32546644). 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	RCV000130923	SCV000185835	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-29	criteria provided, single submitter	clinical testing	The p.A1615T variant (also known as c.4843G>A), located in coding exon 14 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4843. The alanine at codon 1615 is replaced by threonine, an amino acid with similar properties. This variant has been detected in breast and/or ovarian cancer families of Greek, Indian, Brazilian, and Italian ancestry (Ladopoulou A et al. Cancer Lett. 2002 Nov;185(1):61-70; Konstantopoulou I et al. Breast Cancer Res. Treat., 2008 Feb;107:431-41; Juwle A et al. Med. Oncol. 2012 Dec;29(5):3272-81; Silva FC et al. BMC Med. Genet. 2014 May;15:55; D'Argenio V et al. Clin. Chim. Acta. 2015 Jun;446:221-5; Azzollini J et al. Eur. J. Intern. Med. 2016 Jul;32:65-71). One study reports this variant to have functional transcriptional activation (Woods NT et al. NPJ Genom Med . 2016 Mar;1). This amino acid position is well 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.
GeneDx	RCV000586352	SCV000292821	uncertain significance	not provided	2020-05-27	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 4962G>A; Observed in individuals with personal or family history of breast or ovarian cancer (Ladopoulou 2002, Juwle 2012, Silva 2014, D'Argenio 2015, Azzollini 2016); Published functional studies suggest no damaging effect: transactivation activity similar to wildtype (Woods 2016); This variant is associated with the following publications: (PMID: 22752604, 12142080, 24884479, 25896959, 17453335, 30765603, 28781887, 27062684)
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000413325	SCV000492488	uncertain significance	Breast neoplasm		criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000130923	SCV000683221	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-07	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1615 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Functional studies have reported that this variant does not impact BRCA1 function in transcription activation and mouse Brca1-deficient mouse embryonic stem cells in PARP inhibitors sensitivity and homology-directed DNA repair assays (PMID: 28781887, 29884841, 32546644). This variant has been reported in at least four individuals affected with breast cancer (PMID: 12142080, 22752604, 24884479, 25896959; Color internal data) and in a breast cancer case-control meta-analysis in 4/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_002131). This variant has been identified in 1/251402 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	RCV002247445	SCV000699178	uncertain significance	not specified	2024-04-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4843G>A (p.Ala1615Thr) results in a non-conservative amino acid change in 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 4e-06 in 251402 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4843G>A has been reported in the literature in individuals affected with breast and/or ovarian cancers and/or with a family history of BRCA-related cancers (e.g. Ladopoulou_2002, Juwle_2012, Silva_2014, Dargenio_2015, Azzollini_2016, Bisgin_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Publications report experimental evidence evaluating an impact on protein function (Fernandez_2019, Bouwman_2020). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 12142080, 22752604, 24884479, 25896959, 28781887, 27062684, 32546644, 32806537, 35753294, 30765603). ClinVar contains an entry for this variant (Variation ID: 55302). Based on the evidence outlined above, the variant was classified as uncertain significance.
Illumina Laboratory Services, Illumina	RCV000083213	SCV001287203	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586352	SCV001470001	uncertain significance	not provided	2019-09-28	criteria provided, single submitter	clinical testing
Mendelics	RCV002247445	SCV002517945	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483064	SCV002793812	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-04-18	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149708	SCV003838895	uncertain significance	Breast and/or ovarian cancer	2021-10-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000083213	SCV004212718	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000083213	SCV004817621	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1615 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant does not impact BRCA1 function in transcription activation and mouse Brca1-deficient mouse embryonic stem cells in PARP inhibitors sensitivity and homology-directed DNA repair assays (PMID: 28781887, 29884841, 32546644). This variant has been reported in at least four individuals affected with breast cancer (PMID: 12142080, 22752604, 24884479, 25896959; Color internal data) and in a breast cancer case-control meta-analysis in 4/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_002131). This variant has been identified in 1/251402 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)	RCV000083213	SCV000115287	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083213	SCV000145196	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-08-23	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000235839	SCV000591542	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Ala1615Thr variant was identified in the literature in one proband with hereditary breast or ovarian cancer (Ladopoulou 2002). The variant was identified in dbSNP (ID: rs80356987) “With Uncertain significance allele”, the ClinVar database (classified with uncertain significance by Ambry Genetics; classified with uncertain significance by the Sharing Clinical Reports Project, derived from Myriad reports), the BIC database (2X with unknown clinical importance), and UMD (1X as an unclassified variant). The p.Ala1615 residue is conserved in mammals but not conserved in lower organisms and the variant amino acid threonine (Thr) is present in African clawed frog and purple sea urchin, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the significance of this variant, although 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.
Genetic Services Laboratory, University of Chicago	RCV002247445	SCV003839270	uncertain significance	not specified	2022-08-29	no assertion criteria provided	clinical testing	DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.4843G>A, in exon 15 that results in an amino acid change, p.Ala1615Thr. This sequence change has been reported in individuals with personal and/or family history of breast or ovarian cancer (PMID: 12142080, 17453335, 22752604, 24884479, 25896959, 27062684). This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.0004 % (dbSNP rs80356987). The p.Ala1615Thr change affects a moderately conserved amino acid residue located in a domain of the BRCA1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala1615Thr substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ala1615Thr change remains unknown at this time.
Department of Medical and Surgical Sciences, University of Bologna	RCV000083213	SCV004228361	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-01	no assertion criteria provided	clinical testing	BS3(Strong)+BP1(Strong)+BP5(Moderate) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)