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17-43082418-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_007294.4(BRCA1):c.4343G>A(p.Ser1448Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1448G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

1
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.0270
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 Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.021794528).
BP6
Variant 17-43082418-C-T is Benign according to our data. Variant chr17-43082418-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 125707.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.4343G>A p.Ser1448Asn missense_variant 12/23 ENST00000357654.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.4343G>A p.Ser1448Asn missense_variant 12/231 NM_007294.4 P4P38398-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461584
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727090
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA1)May 29, 2002- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxSep 14, 2016This variant is denoted BRCA1 c.4343G>A at the cDNA level, p.Ser1448Asn (S1448N) at the protein level, and results in the change of a Serine to an Asparagine (AGC>AAC). Using alternate nomenclature, this variant would be defined as BRCA1 4462G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ser1448Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Asparagine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Ser1448Asn occurs at a position that is not conserved and is located in the SCD domain and the regions of interaction with ATM, CHEK2, CDK2 and BRCA2 (Chen 1998, Narod 2004, Clark 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Ser1448Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 16, 2015This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.059
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.42
Cadd
Benign
1.6
Dann
Benign
0.64
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.0044
N
LIST_S2
Benign
0.80
T;T;T;T;T;T;T;T;T;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.022
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.30
T
PROVEAN
Benign
0.23
N;N;N;N;N;N;N;N;N;N
REVEL
Uncertain
0.31
Sift
Benign
1.0
T;T;T;T;T;T;T;T;T;T
Sift4G
Benign
0.98
T;T;T;T;T;T;.;.;T;.
Polyphen
0.0010, 0.0
.;B;.;.;.;B;.;B;.;.
Vest4
0.067
MutPred
0.098
.;Loss of phosphorylation at S1448 (P = 0.0111);Loss of phosphorylation at S1448 (P = 0.0111);.;.;.;.;.;.;.;
MVP
0.13
MPC
0.076
ClinPred
0.087
T
GERP RS
1.9
Varity_R
0.018
gMVP
0.030

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: rs80357354; hg19: chr17-41234435; COSMIC: COSV58794423; COSMIC: COSV58794423; API