17-43093448-C-T

Variant names:

• chr17-43093448-C-T
• rs28897681
• NM_007294.4:c.2083G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

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. 14/22 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. D695G) 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:7
• Conservation: PhyloP100: 0.760
• Publications: 27 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -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 VariationId is 54455.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.2083G>A	p.Asp695Asn	missense_variant	Exon 10 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.2083G>A	p.Asp695Asn	missense_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152164 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 251166 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461746 Hom.: 0 Cov.: 42 AF XY: 0.00000413 AC XY: 3 AN XY: 727174

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111938

Other (OTH) AF: 0.0000497 AC: 3 AN: 60390

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74338

African (AFR) AF: 0.0000724 AC: 3 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:2

Aug 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 14, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Nov 21, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 23, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

not provided Benign:4

Aug 03, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 31, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23867111, 9523200, 26689913, 15385441)

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2

Apr 06, 1999

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 09, 2015

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Breast neoplasm Uncertain:1

Sep 05, 2017

3DMed Clinical Laboratory Inc

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

BRCA1-related disorder Uncertain:1

Nov 11, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 27, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 variant was also observed in 1 individual over 70 years of age with no personal history of cancer (FLOSSIES database). 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 presumed heterozygous state in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Chen_2019, Greenman_1998, BIC database), without strong evidence for causality. In at least 1 family with this variant, 2 transmissions of the variant allele and 1 transmissions of the reference allele to affected individuals was reported (Greenman_1998). These data do not allow any conclusion about variant significance. At least one functional study reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant on homology directed repair (HDR) activity (e.g. Lu_2015, Bouwman_2013, Bouwman_2020). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. The following publications have been ascertained in the context of this evaluation (PMID: 23867111, 31867841, 9523200, 26689913, 27300552, 32546644). 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	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.;.;.;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.87	D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.10	T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.6	L;L;.;.;.
PhyloP100		0.76
PrimateAI	Benign	0.26	T
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;.
Vest4		0.23
ClinPred		0.055	T
GERP RS		1.4
Varity_R		0.070
gMVP		0.090
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

dbSNP: rs28897681; hg19: chr17-41245465; COSMIC: COSV58788084;