Submissions for variant NM_007294.4(BRCA1):c.5123C>T (p.Ala1708Val)

gnomAD frequency: 0.00008  dbSNP: rs28897696

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048803	SCV000076816	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1708 of the BRCA1 protein (p.Ala1708Val). This variant is present in population databases (rs28897696, gnomAD 0.03%). This missense change has been observed in individual(s) with a personal and/or family history of breast cancer and/or kidney cancer (PMID: 16489001, 18036263, 22034289, 26287763, 26689913, 27495310). This variant is also known as 5242C>T (A1708V). ClinVar contains an entry for this variant (Variation ID: 37640). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 18036263, 20516115, 26689913, 30209399). This variant disrupts the p.Ala1708 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1157798, 11802208, 15923272, 19404736, 23867111). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	RCV000131166	SCV000186111	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-03	criteria provided, single submitter	clinical testing	The p.A1708V variant (also known as c.5123C>T), located in coding exon 16 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5123. The alanine at codon 1708 is replaced by valine, an amino acid with similar properties. This alteration impacts the functionally important BRCT domain and has been associated with reduced/partial BRCA1 function, suggesting that p.A1708V may act as a low or moderate disease risk allele (Lovelock PK et al. Breast Cancer Res. 2007;9:R82; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Lu C et al. Nat Commun. 2015 Dec;6:10086). Based on one functional study using saturation genome editing, this alteration does not affect the BRCA1 protein (Findlay GM et al. Nature. 2018 10;562:217-222). Of note, this alteration is also known as 5242C>T in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence conflicting at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000589633	SCV000210201	uncertain significance	not provided	2024-06-27	criteria provided, single submitter	clinical testing	Published functional studies showed mixed results with respect to folding ability, binding activity and specificity, homologous recombination repair activity, transcriptional activation, centrosome amplification, foci formation in response to DNA damage, and cell survival (PMID: 18036263, 20516115, 26689913, 28781887, 30209399, 30458859, 30765603, 30257991, 35665744, 37085799); Observed in individuals with a personal and/or family history of breast and other cancers (PMID: 16489001, 22034289, 26689913, 26287763, 35918668, 37719058); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5242C>T; This variant is associated with the following publications: (PMID: 24607278, 22889855, 17403394, 26689913, 26287763, 30263132, 29625052, 16489001, 18036263, 20516115, 22034289, 25637381, 20522429, 15744030, 12161611, 24055113, 28024868, 27720647, 27495310, 28781887, 30209399, 30458859, 30765603, 23867111, 21702907, 15923272, 11802208, 31409081, 30257991, 30678073, 32377563, 35665744, 37085799, 35918668, 36451132, 34621001, 37719058, 1157798, 34981296, 25348405)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212194	SCV000494396	uncertain significance	not specified	2023-12-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5123C>T (p.Ala1708Val) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251672 control chromosomes (gnomAD). Another BRCA1 missense change at the same residue p.Ala1708Glu (c.5123C>A) is a known pathogenic variant. It must be noted that while p.Ala1708Glu leads to change in amino acid charge (neutral to polar), this variant, (p.Ala1708Val) does not. c.5123C>T has been reported in the literature in individuals affected with breast and/or ovarian and other cancers (example: Caldes_2002, Chenevix-Trench_2006, Lovelock_2007, Fackenthal_2012, Lu_2015, Pal_2015, Jarhelle_2016, Moller_2019, Zhang_2022, Yang_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. This variant was also reported in the FLOSSIES database in women older than age 70 years who have never had cancer. Co-occurrences with pathogenic BRCA2 variants have been observed at our laboratory (c.5641_5644delAAAT, p.Lys1881GlnfsX27; c.8188G>C, p.Ala2730Pro; c.3939_3943delCAAGA, p.Y1313X), while an additional non-specified BRCA2 co-occurrence has been reported by an external laboratory in the ClinVar database (SCV000076816.10), providing supporting evidence for a benign role. Multiple publications have reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect leads to varied outcomes depending upon types of assays performed (example, Lovelock_2007, Lee_2008, Lu_2015, Findlay_2018, Fernandes_2019, Petitalot_2019, Bassi_2023). The variant had normal effect on protein expression and foci formation in response to DNA damage, functional homology directed repair (HDR) activity, but had conflicting results ranging from normal to intermediate/strong effect on transcription, protein folding, centrosome amplification and phosphopeptide binding. For these reasons, a recent study reports this variant among those having an intermediate impact (Petitalot_2019). The possibility of the variant being a hypomorphic mildly causative allele associated with a late onset/variable penetrance cannot be ruled out. The following publications have been ascertained in the context of this evaluation (PMID: 30263132, 25637381, 12161611, 16489001, 24055113, 22034289, 30765603, 30209399, 21702907, 29625052, 27495310, 30458859, 20516115, 15744030, 18036263, 26689913, 30678073, 26287763, 30257991, 17403394, 22889855, 28781887, 11802208, 35918668, 35918668, 37085799).Ten ClinVar submitters have assessed this variant since 2014: all submitters classified the variant as uncertain significance. Some submitters cite overlapping but not identical evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000131166	SCV000688538	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1708 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have reported conflicting findings on the activity of the variant protein on various in vitro and ex vivo assays (PMID: 18036263, 20516115, 26689913, 30209399, 30458859). This variant has been reported in individuals with personal and/or family history of breast or ovarian cancer (PMID: 15744030, 16489001, 17403394, 22034289, 26287763, 27495310) including individuals who also had a BRCA2 pathogenic co-variant (PMID: 15744030, 17403394) and in healthy controls (PMID: 15744030, 24055113, 25637381). This variant has also been reported in an individual affected with kidney renal clear cell carcinoma (PMID: 26689913). A different variant affecting the same codon (p.Ala1708Glu) is considered to be disease-causing (ClinVar variation ID: 55407), suggesting that alanine or similar amino acid at this position is important for the protein function. This variant has been identified in 8/282694 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000048803	SCV000891002	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-08-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589633	SCV001133610	uncertain significance	not provided	2023-12-13	criteria provided, single submitter	clinical testing	The BRCA1 c.5123C>T (p.Ala1708Val) variant has been reported in the published literature in individuals affected with breast cancer (PMID: 17403394 (2007), 22034289 (2012), 26287763 (2015), 27495310 (2016), and kidney cancer (PMID: 26689913 (2015), 29625052 (2018)). Assessment of experimental analysis yielded conflicting results regarding the impact of this variant on protein function (PMID: 18036263 (2007), 20516115 (2010), 22889855 (2012), 26689913 (2015), 30209399 (2018), 30458859 (2018), 30257991 (2018)). The frequency of this variant in the general population, 0.00028 (7/24954 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031221	SCV001429075	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2018-07-09	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212194	SCV002064591	uncertain significance	not specified	2020-06-09	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.5123C>T, in exon 17 that results in an amino acid change, p.Ala1708Val. This sequence change has been described in patients with a personal and/or family history of breast cancer, as well as in control populations undergoing exome sequencing (PMIDs: 25637381, 24055113). PMID 20516115 demonstrated a severe folding defect and compromised binding activity and binding specificity associated with the p.Ala1708Val change. However, PMID 18036263 demonstrated an intermediate effect on transcriptional transactivation associated with the p.Ala1708Val change, more suggestive of a low or moderate risk allele. This sequence change has been described in the gnomAD database with a low population frequency of 0.03% (dbSNP rs28897696). The p.Ala1708Val change affects a highly conserved amino acid residue located in a domain of the BRCA1 protein that is known to be functional. The p.Ala1708Val substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ala1708Val change remains unknown at this time.
Sema4, Sema4	RCV000131166	SCV002537814	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-15	criteria provided, single submitter	curation
Baylor Genetics	RCV000031221	SCV004212680	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004802992	SCV004817586	uncertain significance	BRCA1-related cancer predisposition	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1708 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported conflicting findings on the activity of the variant protein on various in vitro and ex vivo assays (PMID: 18036263, 20516115, 26689913, 30209399, 30458859). This variant has been reported in individuals with personal and/or family history of breast or ovarian cancer (PMID: 15744030, 16489001, 17403394, 22034289, 26287763, 27495310) including individuals who also had a BRCA2 pathogenic co-variant (PMID: 15744030, 17403394) and in healthy controls (PMID: 15744030, 24055113, 25637381). This variant has also been reported in an individual affected with kidney renal clear cell carcinoma (PMID: 26689913). A different variant affecting the same codon (p.Ala1708Glu) is considered to be disease-causing (ClinVar variation ID: 55407), suggesting that alanine or similar amino acid at this position is important for the protein function. This variant has been identified in 8/282694 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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000589633	SCV005199700	uncertain significance	not provided	2022-10-04	criteria provided, single submitter	clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000031221	SCV005402479	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-04-12	criteria provided, single submitter	curation	Each variant was annotated with functional scores from MAVE data which was translated into functional evidence codes. All other evidence codes and combining criteria were adhered to as closely as possible based on the ClinGen VCEP (Variant Curation Expert Panel) gene-specific recommendations. See Supplemental Figure 34 of final paper (Supp Fig. 28 in preprint: doi:10.1101/2024.04.11.24305690) for a table to see which lines of evidence we did not have data for. The ClinGen VCEPs are highly regarded as the gold-standard for gene-specific variant curation and are developed after extensive evaluation of the evidence by clinical and scientific experts for the particular gene to classify genomic variants on a spectrum from pathogenic to benign using the 2015 ACMG/AMP Variant Interpretation Guidelines as a backbone (PMID: 25741868). Reclassification of these VUS variants from gnomAD or All of Us focused only on variants originally prescribed as VUS in ClinVar. To ensure reproducibility, transparency, and increased throughput, all the procedures for annotating variants and assigning evidence codes were codified using Python. All code has been made freely available and is linked in the Code Availability section and all reclassified variants with evidence codes used can be found in Tables S18-19 (preprint: doi:10.1101/2024.04.11.24305690). For the MAVE data, the clinical curation and clinical strength assignment as per the ClinGen recommendations in Brnich et al. (2020) (PMID: 31892348) for or against pathogenicity or benignity of each of these MAVE datasets utilized in this study were previously published in Fayer et al. (2021) (PMID: 34793697).In brief, for BRCA1 variants, if a variant was categorized as FUNC (functional), it was assigned BS3 evidence and no PS3 evidence, whereas if it was categorized as LOF (loss of function), the variant was assigned PS3 evidence and no BS3 evidence. Variants categorized as INT (intermediate) were left unannotated. For the BRCA1 combining criteria, greater than or equal to 1 criteria of strong benign evidence was enough to reclassify the VUS as Likely Benign. This variant GRCh38:17:43063903:G>A was assigned evidence codes ['BS3', 'BS1_Supporting'] and an overall classification of Likely benign
Fulgent Genetics, Fulgent Genetics	RCV005016313	SCV005647120	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2024-02-21	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031221	SCV000053821	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148393	SCV000190092	uncertain significance	Breast and/or ovarian cancer	2014-06-01	no assertion criteria provided	research
Department of Medical Genetics, University Hospital of North Norway	RCV000031221	SCV000301438	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-05-01	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000212194	SCV000587467	uncertain significance	not specified	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353479	SCV000591584	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Ala1708Val variant was identified in 1 of 2000 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer, and was not identified in 180 control chromosomes from healthy individuals (Dorschner 2013); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant was also identified in dbSNP (ID: rs28897696) “With Pathogenic, Uncertain significance allele”, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, HGMD, LOVD, the ClinVar database (classified as a uncertain significance variant by the Sharing Clinical Reports Project, derived from Myriad reports; Ambry Genetics; CSER_CC_NCGL and GeneDX), GeneInsight VariantWire database(1X, classified as “unknown significance” by a clinical laboratory) and UMD (2X as a unknown significance variant).This variant was identified in the HAPMAP-JPT in 1 of 168 chromosomes (frequency: 0.006), Exome Variant Server project in 3 of 13006 European American/African American alleles, the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 4 of 10284 chromosomes (frequency: 0.0004) from a population of African individuals, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Ala1708 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Ala1708 variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Functional studies by Chenevix-Trench (2006) and Lee (2010) characterized the variant as unclassified with odds of 41:1 in favor of causality with strong functional effect. In addition, in the study by Lovelock (2007) this variant displayed an intermediate transcriptional transactivation activity and a normal foci formation response in response to DNA damage but induced centrosome amplification. The results of this study also raise the possibility that variant may be associated with a low or moderate risk of cancer. 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.
Brotman Baty Institute, University of Washington	RCV000031221	SCV001242169	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Center for Precision Medicine, Meizhou People's Hospital	RCV002250480	SCV002520922	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only
BRCAlab, Lund University	RCV000031221	SCV004243947	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004758614	SCV005341091	uncertain significance	BRCA1-related disorder	2024-03-27	no assertion criteria provided	clinical testing	The BRCA1 c.5123C>T variant is predicted to result in the amino acid substitution p.Ala1708Val. This variant has been reported in individuals with a personal and/or family history of breast cancer and/or ovarian cancer (Chenevix-Trench et al. 2006. PubMed ID: 16489001; Lovelock et al. 2007. PubMed ID: 18036263; Fackenthal et al. 2012. PubMed ID: 22034289, Jarhelle et al. 2017. PubMed ID: 27495310), and an individual with renal cancer (Lu et al. 2015. PubMed ID: 26689913). It has also been detected as an incidental finding in exome cohorts and interpreted as uncertain significance (Dorschner et al. 2013. PubMed ID: 24055113; Amendola. 2015. PubMed ID: 25637381). The results of functional studies of this variant are conflicting (Lovelock et al. 2007. PubMed ID: 18036263; Lee et al. 2010. PubMed ID: 20516115; Lu et al. 2015. PubMed ID: 26689913. Findlay et al. 2018. PubMed ID: 30209399). This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD and interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37640/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.