17-43092077-C-T

Variant names:

• chr17-43092077-C-T
• rs80357175
• NM_007294.4:c.3454G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BP6

The NM_007294.4(BRCA1):​c.3454G>A​(p.Asp1152Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,928 control chromosomes in the GnomAD database, including 1 homozygotes. 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. D1152E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (1 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:9
• Conservation: PhyloP100: 2.50
• Publications: 20 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32702023).
• BP6: Variant 17-43092077-C-T is Benign according to our data. Variant chr17-43092077-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 54890.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.3454G>A	p.Asp1152Asn	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.3454G>A	p.Asp1152Asn	missense_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152192 Hom.: 0 Cov.: 32

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251258 AF XY: 0.0000368

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461736 Hom.: 1 Cov.: 39 AF XY: 0.0000275 AC XY: 20 AN XY: 727180

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

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

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68038

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

Alfa AF: 0.0000831 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:4 Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 09, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.3454G>A; p.Asp1152Asn variant (rs80357175), also known as 3573G>A in traditional nomenclature, is reported in the literature in multiple individuals affected with breast and/or ovarian cancer, as well as one pediatric patient with leukemia (Borg 2010, Kluska 2015, Stegel 2011, Zhang 2015). This variant is reported as uncertain significance by multiple laboratories in ClinVar (Variation ID: 54890), and is found in the non-Finnish European population with an allele frequency of 0.0085% (11/129,078 alleles) in the Genome Aggregation Database. The aspartic acid at codon 1152 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. In vitro functional analyses demonstrate activity similar to wildtype in a homology-directed repair assay (Lu 2015). Due to limited information, the clinical significance of the p.Asp1152Asn variant is uncertain at this time. References: Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. Kluska A et al. New recurrent BRCA1/2 mutations in Polish patients with familial breast/ovarian cancer detected by next generation sequencing. BMC Med Genomics. 2015 May 7;8:19. Lu C et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun. 2015 Dec 22;6:10086. Stegel V et al. The occurrence of germline BRCA1 and BRCA2 sequence alterations in Slovenian population. BMC Med Genet. 2011 Jan 14;12:9. Zhang J et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med. 2015 Dec 10;373(24):2336-2346. -

Apr 20, 2017

Department of Pathology and Molecular Medicine, Queen's University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 06, 2024

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.3454G>A (p.Asp1152Asn) 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 2.7e-05 in 1607012 control chromosomes in the gnomAD database (v4.1 dataset), including 1 homozygote. This frequency is not higher than the estimated maximum expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (0.001), however the presence of the variant in a homozygote suggests that it might be benign. c.3454G>A has been reported in the literature in individuals affected with breast and/or ovarian cancer without strong evidence for causality (e.g. Hansen_2009, Borg_2010, Stegel_2011, Wong-Brown_2015, Kluska_2015, Zhang_2015, Santonocito_2020, Hauke_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 6/60466 cases, but was also found in 5/53461 controls (Dorling_2021, reported through LOVD). A co-occurrence with a likely pathogenic variant (BRCA1 c.4485_4675del, p.Ser1496GlyfsX14, which corresponds to the deletion of exon 14) has also been reported, providing supporting evidence for a benign role (UMD database). Although, a recent in vitro expression study found reduced protein levels and increased proteasomal degradation for the variant protein (Hovland_2023), earlier studies demonstrated no damaging effect of this variant on homology directed repair (HDR) activity, and no impairment on its ability to complement BRCA1-deficient mouse embryonic stem cells in homologous recombination DNA repair (HRR) using cisplatin and olaparib sensitivity assays and a direct GFP HRR assay (e.g. Lu_2015, 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: 15235020, 20104584, 32546644, 21520273, 12531920, 18500671, 33273034, 25948282, 26689913, 15385441, 32438681, 21232165, 23704879, 25682074, 26580448, 36833189, 33471991). ClinVar contains an entry for this variant (Variation ID: 54890). Based on the evidence outlined above, the variant was classified as likely benign. -

Sep 29, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3 Benign:2

May 01, 2018

MVZ Praenatalmedizin und Genetik Nuernberg

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This rare variant (gnomAD) was found multiple times in databases and literature with uncertain significance. In silico analyses show contradictory results. Therefore we rate this variant as Variant of unknown significance (VUS). Interestingly we found this variant in a patient who harbored also a pathogenic BRCA2-variant (NM_000059.3 c.5238dupT het) -

Nov 24, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 14, 2010

Sharing Clinical Reports Project (SCRP)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:3 Benign:1

Apr 10, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20104584, 18500671, 15235020, 25948282, 21232165, 26689913, 26580448, 26941049, 21520273, 25682074, 23704879, 15385441) -

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA1: PM2, BP1 -

May 18, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 18, 2017

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4

Apr 28, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 11, 2020

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 03, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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. -

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). -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA1 p.Asp1152Asn variant was identified in 1 of 1042 proband chromosomes (frequency: 0.001) from Slovenian individuals or families with breast and/or ovarian cancers, and was not identified in 80 control chromosomes from healthy individuals (Stegel 2011). The variant was identified by our laboratory in 2 individuals with breast cancer. The variant was also identified in dbSNP (ID: rrs80357175 “With Uncertain significance allele”. The variant was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 2 of 121314 chromosomes (frequency: 0.00001649) or 2 of 66712 European (Non-Finnish) alleles and was not found in populations of South Asians, East Asian, African, Latino, European (Finnish) and other individuals. The p.Asp1152Asn variant was identified in the Clinvar database and was classified as a variant of uncertain significance by Ambry Genetics, GeneDx and BIC; Invitae did not provide a classification. The BRCA Share UMD database identified the variant 3X and classified it as unknown; the variant was identified with a co-occurring BRCA1 pathogenic variant (c.4485_4675del, p.Ser1496GlyfsX14), increasing the likelihood that the p.Asp1152Asn variant does not have clinical significance. BIC database identified the variant 3X with unknown clinical importance. The p.Asp1152 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In addition, evolutionary conservation analysis predicts the variant as neutral (Abkevich 2004). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Familial cancer of breast Uncertain:1

Sep 16, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,BP1. -

Hereditary breast ovarian cancer syndrome Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;.;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.0	M;M;.;.
PhyloP100		2.5
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-4.1	D;D;D;D
REVEL	Uncertain	0.37
Sift	Benign	0.095	T;T;T;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.20	B;.;.;B
Vest4		0.41
MutPred		0.46		Loss of phosphorylation at T1149 (P = 0.122);Loss of phosphorylation at T1149 (P = 0.122);.;Loss of phosphorylation at T1149 (P = 0.122);
MVP		0.82
MPC		0.13
ClinPred		0.42	T
GERP RS		4.3
PromoterAI		-0.019	Neutral
Varity_R		0.18
gMVP		0.10
Mutation Taster		=60/40	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: rs80357175; hg19: chr17-41244094; COSMIC: COSV58798983;