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rs1799966

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM5BP4_ModerateBP6_Very_Strong

The NM_007294.4(BRCA1):c.4837A>T(p.Ser1613Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1613A?) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

1
6
10

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:10

Conservation

PhyloP100: -0.194
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 Benign. Variant got -8 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43071076-CT-GGC is described in ClinVar as [Pathogenic]. Clinvar id is 180697.Status of the report is reviewed_by_expert_panel, 3 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.17928162).
BP6
Variant 17-43071077-T-A is Benign according to our data. Variant chr17-43071077-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 37613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.4837A>T p.Ser1613Cys missense_variant 15/23 ENST00000357654.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.4837A>T p.Ser1613Cys missense_variant 15/231 NM_007294.4 P4P38398-1

Frequencies

GnomAD3 genomes
AF:
0.000184
AC:
28
AN:
151990
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000677
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:
0.0000517
AC:
13
AN:
251384
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135858
show subpopulations
Gnomad AFR exome
AF:
0.000800
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000144
AC:
21
AN:
1461884
Hom.:
0
Cov.:
59
AF XY:
0.0000124
AC XY:
9
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.000538
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000184
AC:
28
AN:
151990
Hom.:
0
Cov.:
32
AF XY:
0.000243
AC XY:
18
AN XY:
74216
show subpopulations
Gnomad4 AFR
AF:
0.000677
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
ExAC
AF:
0.0000659
AC:
8

ClinVar

Significance: Benign/Likely benign
Submissions summary: Uncertain:1Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthOct 06, 2016- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 01, 2018This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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. -
Likely benign, criteria provided, single submittercurationSema4, Sema4Jul 07, 2021- -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:1
Uncertain significance, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA1)Feb 20, 2004- -
Benign, no assertion criteria providedclinical testingSharing Clinical Reports Project (SCRP)Nov 14, 2011- -
not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 11, 2024Variant summary: BRCA1 c.4837A>T (p.Ser1613Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251384 control chromosomes, predominantly at a frequency of 0.0008 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (5.2e-05 vs 0.001), allowing no conclusion about variant significance. c.4837A>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity. ClinVar contains an entry for this variant (Variation ID: 37613). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoApr 18, 2019- -
BRCA1-related condition Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 01, 2021This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxDec 18, 2020This variant is associated with the following publications: (PMID: 26092435, 31705708, 15004537, 15350310, 19370767, 10728701, 21447777, 18992264, 25896959, 15617999, 9326340, 26183948, 28781887, 30765603, 31706072) -
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The BRCA1 p.Ser1613Cys variant was identified in 1 of 140 proband chromosomes (frequency: 0.007) from individuals or families with breast cancer (D'Argenio 2015). The variant was also identified in dbSNP (rs1799966) as “other”, in ClinVar with conflicting interpretations of pathogenicity (5 submitters, classified as Likely Benign by Invitae, Ambry, and GeneDx, classified as Uncertain Significance by BIC and as Benign by the Sharing Clinic Reports Project), in Clinvitae (classified as Likely benign as reported in ClinVar) and in BIC (4x classified as unknown), the Fanconi Anemia Mutation Database (3x classified as predicted neutral) databases. The variant was also identified in the control database the Exome Aggregation Consortium (ExAC) in 8 of 121360 chromosomes (freq. 0.00007), all cases were seen in the African population specifically 8 of 10406 chromosomes (freq. 0.0008), increasing the likelihood that this may be a low frequency benign variant. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the ARUP Laboratories BRCA Mutations Database, COSMIC, GeneInsight COGR, and UMD. Functional studies initially reported the p.Ser1613Cys variant to be disease causing based on a transcription activation assay performed in yeast (Monteiro 1997). However a more recent and more sensitive transcriptional assay reported the p.Ser1613Cys variant to be likely neutral and noted that the sensitivity of the previous assay was likely the reason for the conflicting results (Carvalho 2009). The p.Ser1613 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. Moreover this locus is the known site of a common polymorphism in BRCA1 p.Ser1613Gly (identified in 35% of cases in ExAC) and classified as Benign by our laboratory. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 21, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Uncertain
-0.080
Cadd
Benign
16
Dann
Benign
0.97
Eigen
Benign
-0.42
Eigen_PC
Benign
-0.60
FATHMM_MKL
Benign
0.055
N
LIST_S2
Benign
0.76
T;T;T;T;T;T;T;T;T;T
M_CAP
Pathogenic
0.63
D
MetaRNN
Benign
0.18
T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.022
D
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.29
T
PROVEAN
Uncertain
-3.0
D;N;.;N;.;N;D;D;N;N
REVEL
Uncertain
0.51
Sift
Uncertain
0.0020
D;D;.;D;.;D;D;D;D;D
Sift4G
Uncertain
0.044
D;D;D;T;D;D;D;.;.;T
Polyphen
0.98, 0.98
.;D;.;.;.;.;.;.;D;.
Vest4
0.31
MVP
0.78
MPC
0.37
ClinPred
0.095
T
GERP RS
1.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.087
gMVP
0.32

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs1799966; hg19: chr17-41223094; API