rs80356865

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP6

The NM_007294.4(BRCA1):c.734A>T(p.Asp245Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,144 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D245E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:2

Conservation

PhyloP100: 1.10

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]

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.33007848).

BP6

Variant 17-43094797-T-A is Benign according to our data. Variant chr17-43094797-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55682.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=8, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.734A>T	p.Asp245Val	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.734A>T	p.Asp245Val	missense_variant	10/23	1	NM_007294.4	P4	P38398-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250038

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135248

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461144

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726920

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:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jun 20, 2002	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Medical Genetics, University Hospital of North Norway	May 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 2023	This missense variant replaces aspartic acid with valine at codon 245 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). Functional study has shown this variant has neutral effect on DNA interstrand crosslink (ICL) repair (PMID: 23867111). This variant has been reported in at least four individuals affected with breast or ovarian cancer and one unaffected individual (PMID: 26843898, 32806537, 33471991; Color internal data; LOVD DB-ID: BRCA1_001285) and an individual with family history of breast or ovarian cancer (PMID: 27495310). This variant has been identified in 3/250038 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 submitter	clinical testing	Counsyl	Dec 16, 2015	- -

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 01, 2023	In the published literature, the variant has been reported in individuals with personal or family history of breast or ovarian cancer (PMID: 32806537 (2020), 27495310 (2016), 26843898 (2016), 25415331 (2014)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in an unaffected individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA1)). A functional study has reported that this variant does not have a deleterious effect on BRCA1 protein function (PMID: 23867111 (2013)). The frequency of this variant in the general population, 0.000027 (3/113104 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 submitter	clinical testing	GeneDx	Sep 22, 2022	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate no damaging effect (Bouwman et al., 2013); Also known as 853A>T; Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Jarhelle et al., 2016; Wojcik et al., 2016; Foglietta et al., 2020); This variant is associated with the following publications: (PMID: 27495310, 26843898, 22703879, 32806537, 31131967, 9926942, 9582019, 9788437, 20215511, 23867111) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 20, 2023	The p.D245V variant (also known as c.734A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 734. The aspartic acid at codon 245 is replaced by valine, an amino acid with highly dissimilar properties. This alteration has been identified in individuals with a personal or family history of breast and/or ovarian cancer (Wojcik P et al. Hered Cancer Clin Pract, 2016 Feb;14:5; Jarhelle E et al. Fam. Cancer, 2017 01;16:1-16; Foglietta J et al. Genes (Basel), 2020 08;11; Hovland HN et al. Fam Cancer, 2022 Oct;21:389-398; Boga I et al. Eur J Breast Health, 2023 Jul;19:235-252). This amino acid position is well 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 11, 2023	This missense variant replaces aspartic acid with valine at codon 245 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). A functional study has shown this variant has neutral effect on DNA interstrand crosslink (ICL) repair (PMID: 23867111). This variant has been reported in multiple individuals affected with breast or ovarian cancer, as well as one unaffected individual (PMID: 26843898, 32806537, 33471991; LOVD DB-ID: BRCA1_001285) and an individual with family history of breast or ovarian cancer (PMID: 27495310). This variant has been identified in 3/250038 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. -
Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

Hereditary breast ovarian cancer syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 245 of the BRCA1 protein (p.Asp245Val). This variant is present in population databases (rs80356865, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 26843898, 27495310). ClinVar contains an entry for this variant (Variation ID: 55682). 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 have shown that this missense change does not substantially affect BRCA1 function (PMID: 23867111). 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. -
Benign, criteria provided, single submitter	curation	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Sep 09, 2024	According to the ClinGen ENIGMA BRCA1 v1.1.0 criteria we chose these criteria: BP1 (strong benign): no impact on splicing (SpliceAI), outside functional domain , BS3 (strong benign): Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID:32546644) (BS3 met). -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 09, 2020

Variant summary: BRCA1 c.734A>T (p.Asp245Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250038 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.734A>T has been reported in the literature in patients with a family history or women diagnosed with breast or ovarian cancer (Jarhelle_2016, Wojcik_2016). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. In a cDNA-based functional assay, to classify the BRCA1 VUSs based on their ability of functionally complement BRCA1-deficient mouse embryonic stem cells, the variant was found to be neutral (Bouwman_2013). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.25

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.33

T;.;.;.;.;.;T;.;T;.;T;T;.;T

Eigen

Benign

0.012

Eigen_PC

Benign

-0.0089

FATHMM_MKL

Benign

0.55

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.33

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Uncertain

2.4

M;M;M;.;M;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

0.96

D;D;D;D;D;D;D;D;D;D;D;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.5

N;N;N;N;N;N;N;D;D;N;.;N;N;N

REVEL

Uncertain

0.62

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;.;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;.;.;D;.;D;.;D;.;D

Polyphen

0.98

D;.;.;.;D;.;D;.;.;P;.;.;.;.

Vest4

0.53

MutPred

0.27

Loss of glycosylation at T248 (P = 0.1096);Loss of glycosylation at T248 (P = 0.1096);Loss of glycosylation at T248 (P = 0.1096);.;Loss of glycosylation at T248 (P = 0.1096);.;.;.;.;Loss of glycosylation at T248 (P = 0.1096);.;Loss of glycosylation at T248 (P = 0.1096);.;Loss of glycosylation at T248 (P = 0.1096);

MVP

0.87

MPC

0.52

ClinPred

0.80

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.37

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over