17-43093448-C-T

Position:

chr17-43093448-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_007294.4(BRCA1):c.2083G>A(p.Asp695Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. D695Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:7

Conservation

PhyloP100: 0.760

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:

BRCA1 (HGNC:):

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.104191124).

BP6

Variant 17-43093448-C-T is Benign according to our data. Variant chr17-43093448-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54455.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=5, Benign=1}. Variant chr17-43093448-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.2083G>A	p.Asp695Asn	missense_variant	10/23	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.2083G>A	p.Asp695Asn	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251166

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135732

show subpopulations

Gnomad AFR exome

AF:

0.000246

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:

0.00000881

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461746

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.0000329

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Mar 14, 2022	- -
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). -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 21, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 21, 2023	The p.D695N variant (also known as c.2083G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 2083. The aspartic acid at codon 695 is replaced by asparagine, an amino acid with highly similar properties. This alteration was reported in one hereditary breast ovarian cancer family from South Africa, however it segregated with disease in only two of three affected sisters and ethnically matched controls were not available (Greenman J et al. Genes Chromosomes Cancer. 1998 Mar;21(3):244-9). In an additional study, this alteration was reported as neutral based on several functional assays assessing the effect of p.D695N on BRCA1-selectable conditional knockout mouse embryonic stem cells (Bouwman P et al. Cancer Discov. 2013 Oct;3(10):1142-55). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2020	This variant is associated with the following publications: (PMID: 23867111, 9523200, 26689913, 15385441) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 03, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 09, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Apr 06, 1999	- -

Breast neoplasm

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

3DMed Clinical Laboratory Inc

Sep 05, 2017

- -

BRCA1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2022

The BRCA1 c.2083G>A variant is predicted to result in the amino acid substitution p.Asp695Asn. This variant was reported in individuals with breast cancer/ovarian cancer (reported as D695N in Table 1, Greenman et al 1998. PubMed ID: 9523200; Table1, Bouwman et al 2013. PubMed ID: 23867111; Supplementary Data File S1, Kim et al 2020. PubMed ID: 31907386; Table S1, Dong et al 2020. PubMed ID: 32467295). Functional studies suggested that p.Asp695Asn variant does not affect normal HDR activity (Table S22, Lu et al. 2015. PubMed ID: 26689913; Table S2, Bouwman et al 2020. PubMed ID: 32546644). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-41245465-C-T). In ClinVar, this variant is interpreted as benign/likely benign/uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/54455/?new_evidence=false). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 695 of the BRCA1 protein (p.Asp695Asn). This variant is present in population databases (rs28897681, gnomAD 0.02%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9523200, 31907386). ClinVar contains an entry for this variant (Variation ID: 54455). 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, 26689913, 32546644). 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Apr 30, 2024

Variant summary: BRCA1 c.2083G>A (p.Asp695Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251166 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2083G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Greenman 1998) and colorectal carcinoma (Wei_2016). Greenman_1998 reports a family of three affected sisters, which one of the affected sisters did not carry the variant of interest, therefore, suggesting lack of cosegregation with disease. Two functional studies found the variant to not affect HDR activity (Lu_2015) and can rescue proliferation (Bouwman_2013). The following publications have been ascertained in the context of this evaluation (PMID: 23867111, 9523200, 26689913, 27300552, 31867841). ClinVar contains an entry for this variant (Variation ID: 54455). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;.;.;.;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.14

LIST_S2

Uncertain

0.87

D;D;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.10

T;T;T;T;T

MetaSVM

Benign

-0.54

MutationAssessor

Benign

1.6

L;L;.;.;.

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-3.7

D;D;D;D;.

REVEL

Benign

0.25

Sift

Benign

0.066

T;T;T;T;.

Sift4G

Benign

0.073

T;T;T;T;.

Polyphen

0.93

P;.;.;B;.

Vest4

0.23

MutPred

0.34

Gain of MoRF binding (P = 0.0974);Gain of MoRF binding (P = 0.0974);.;Gain of MoRF binding (P = 0.0974);.;

MVP

0.70

MPC

0.18

ClinPred

0.055

GERP RS

1.4

Varity_R

0.070

gMVP

0.090

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