17-43104183-C-T

Variant summary

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

The NM_007294.4(BRCA1):​c.380G>A​(p.Ser127Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

1
13
5

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 4.25
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.380G>A p.Ser127Asn missense_variant 6/23 ENST00000357654.9 NP_009225.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.380G>A p.Ser127Asn missense_variant 6/231 NM_007294.4 ENSP00000350283 P4P38398-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152106
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251430
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135894
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461770
Hom.:
0
Cov.:
33
AF XY:
0.00000963
AC XY:
7
AN XY:
727186
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152106
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74306
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000302
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:4
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthMay 04, 2023This missense variant replaces serine with asparagine at codon 127 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast or ovarian cancer (PMID: 18824701, 31825140). This variant also has been reported in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.1391 and 3.672, respectively (PMID: 31131967). This variant has been identified in 6/251430 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, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA1)Feb 20, 2004- -
Uncertain significance, criteria provided, single submitterclinical testingCounsylNov 08, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMar 04, 2021This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 07, 2022This missense variant replaces serine with asparagine at codon 127 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast or ovarian cancer (PMID: 18824701, 31825140). This variant also has been reported in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.1391 and 3.672, respectively (PMID: 31131967). This variant has been identified in 6/251430 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 testingAmbry GeneticsMar 01, 2023The p.S127N variant (also known as c.380G>A), located in coding exon 5 of the BRCA1 gene, results from a G to A substitution at nucleotide position 380. The serine at codon 127 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been classified as a variant of uncertain significance (p=0.1645) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Spearman AD et al. J. Clin. Oncol. 2008; 26:5393-400; Tavtigian SV et al. Hum. Mutat. 2008; 29:1342-54). 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 is limited at this time, the clinical significance of this alteration remains unclear. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 07, 2023Variant summary: BRCA1 c.380G>A (p.Ser127Asn) results in a 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 2.4e-05 in 251430 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.380G>A has been reported in the literature in individuals affected with breast cancer (example, Spearman_2008, Gao_2020). In one of these studies, the tumor showed LOH of variant allele, suggestive of a neutral impact (Spearman_2008). 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. These results showed no damaging effect of this variant on the E3 ligase activity of BRCA1 although the impact on BARD1 binding and homology directed repair (HDR) activity was not reported (Starita_2015). The following publications have been ascertained in the context of this evaluation (PMID: 18951440, 18824701, 25823446, 31825140). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 08, 2023Observed in a patient with breast cancer (Spearman et al., 2008); Published functional studies demonstrate no damaging effect on E3 ubiquitin ligase activity (Starita et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 499G>A; This variant is associated with the following publications: (PMID: 18824701, 26956035, 15385441, 20215511, 18951440, 31131967, 18951461, 29884841, 32377563, 25823446, 31853058, 31825140) -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 24, 2024This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 127 of the BRCA1 protein (p.Ser127Asn). This variant is present in population databases (rs80357189, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 18824701). ClinVar contains an entry for this variant (Variation ID: 55012). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein 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: 25823446). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.47
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Pathogenic
0.18
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.28
.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.94
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.27
D
MetaRNN
Uncertain
0.49
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.46
T
MutationAssessor
Uncertain
2.5
M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
0.95
D;D;D;D;D;D;D;D;D;N;N;N;N;N
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-1.1
N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;N
REVEL
Uncertain
0.53
Sift
Uncertain
0.017
D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D
Sift4G
Benign
0.063
T;D;D;D;D;D;.;.;D;.;D;.;D;.;D;.
Polyphen
0.96, 0.99, 1.0
.;P;.;.;.;D;.;.;.;.;D;.;.;.;.;.
Vest4
0.62
MVP
0.97
MPC
0.40
ClinPred
0.47
T
GERP RS
5.3
Varity_R
0.33
gMVP
0.38

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: rs80357189; hg19: chr17-41256200; COSMIC: COSV104398482; COSMIC: COSV104398482; API