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rs28897696

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM5PP3

The NM_007294.4(BRCA1):c.5123C>T(p.Ala1708Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,613,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1708E) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

12
3
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:19O:1

Conservation

PhyloP100: 6.18
Variant links:
Genes affected
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 16 uncertain in NM_007294.4
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43063903-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 55407.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.79

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.5123C>T p.Ala1708Val missense_variant 17/23 ENST00000357654.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.5123C>T p.Ala1708Val missense_variant 17/231 NM_007294.4 P4P38398-1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152096
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000266
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
251312
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135846
show subpopulations
Gnomad AFR exome
AF:
0.000369
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000144
AC:
21
AN:
1461684
Hom.:
0
Cov.:
31
AF XY:
0.0000165
AC XY:
12
AN XY:
727164
show subpopulations
Gnomad4 AFR exome
AF:
0.000329
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152096
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74286
show subpopulations
Gnomad4 AFR
AF:
0.000266
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000916
Hom.:
0
Bravo
AF:
0.0000907
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:19Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:6Other:1
Uncertain significance, no assertion criteria providedclinical testingSharing Clinical Reports Project (SCRP)May 01, 2012- -
Uncertain significance, no assertion criteria providedclinical testingDepartment of Medical Genetics, University Hospital of North NorwayMay 01, 2016- -
Uncertain significance, no assertion criteria providedclinical testingBRCAlab, Lund UniversityMar 02, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthNov 20, 2023This 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. -
Uncertain significance, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJul 09, 2018- -
not provided, no classification providedin vitroBrotman Baty Institute, University of Washington-- -
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsOct 24, 2023- -
not specified Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJun 09, 2020DNA 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. -
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 28, 2023Variant 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. -
Uncertain significance, no assertion criteria providedresearchResearch Molecular Genetics Laboratory, Women's College Hospital, University of TorontoJan 31, 2014- -
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 26, 2023The 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 (Lu C et al. Nat Commun. 2015 Dec;6:10086; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Lovelock PK et al. Breast Cancer Res. 2007;9:R82). 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. -
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Jun 15, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJan 18, 2024This 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. -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJan 27, 2023The frequency of this variant in the general population, 0.00028 (7/24954 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported 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)). 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. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxSep 26, 2023Published 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 (Lovelock et al., 2007; Lee et al., 2010; Lu et al., 2015; Woods et al., 2016; Findlay et al., 2018; Langerud et al., 2018; Fernandes et al., 2019; Petitalot et al., 2019; Iversen et al., 2022; Bassi et al., 2023); Observed in individuals with a personal and/or family history of breast and other cancers (Chenevix-Trench et al., 2006; Fackenthal et al., 2012; Lu et al., 2015; Pal et al., 2015; Zhang et al., 2022; Rioki et al., 2023); 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, 25348405, 35665744, 37085799, 35918668, 36451132, 34621001, 37719058, 1157798, 34981296) -
Hereditary breast ovarian cancer syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingInvitaeDec 15, 2023This 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). Advanced modeling performed at Invitae incorporating data from internal and/or published 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. -
Uncertain significance, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalAug 04, 2021- -
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, no assertion criteria providedresearchCSER _CC_NCGL, University of WashingtonJun 01, 2014- -
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-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. -
Familial cancer of breast Uncertain:1
Uncertain significance, no assertion criteria providedliterature onlyCenter for Precision Medicine, Meizhou People's Hospital-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.64
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Pathogenic
0.43
Cadd
Pathogenic
26
Dann
Pathogenic
1.0
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.79
D
MetaRNN
Pathogenic
0.79
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.85
D
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI
Uncertain
0.71
T
PROVEAN
Uncertain
-3.1
D;N;.;D;.;.;N;D;D;N;D
REVEL
Pathogenic
0.79
Sift
Benign
0.037
D;D;.;D;.;.;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;.;.;D
Polyphen
1.0, 1.0
.;D;.;.;.;D;.;.;.;D;.
Vest4
0.94
MVP
0.97
MPC
0.38
ClinPred
0.59
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.79
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs28897696; hg19: chr17-41215920; COSMIC: COSV58790852; COSMIC: COSV58790852; API