17-43093408-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_007294.4(BRCA1):c.2123C>A(p.Ser708Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. S708C) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:13

Conservation

PhyloP100: -0.143

Publications

18 publications found

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 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

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05251029).

BP6

Variant 17-43093408-G-T is Benign according to our data. Variant chr17-43093408-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 37447.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.2123C>A	p.Ser708Tyr	missense_variant	Exon 10 of 23	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 link	c.2123C>A	p.Ser708Tyr	missense_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.0000677

AC:

AN:

251170

AF XY:

0.0000810

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.000406

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1111984

Other (OTH)

AF:

0.0000497

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.0000656

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68016

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000186

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:6

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). -

Apr 23, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Apr 22, 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. -

Nov 15, 2016

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 25, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP4, BS1, BS3, BP1_Strong c.2123C>A, located in exon 10 (11 according BIC nomenclature) of the BRCA1 gene, is predicted to result in the substitution of serine by tyrosine at codon 708, p.(Ser708Tyr). This position is outside a (potentially) clinically important functional domain and, moreover, the SpliceAI algorithm predicts no significant impact on splicing (BP1_strong). The variant allele was found in 12/30518 alleles, with a filter allele frequency of 0.0178% at 99% confidence, within the South Asian population in the gnomAD v2.1.1 database (non-cancer data set) (BS1). BRCA1 c.2123C>A was reported by one calibrated study to affect protein function similar to benign control variants (PMID: 32546644) (BS3). Published clinical data for a multifactorial likelihood analysis (PMID: 31131967) showed a combined LR indicative of supporting evidence towards pathogenicity (LR 3.73), based on tumour characteristics (LR 3.73) (PP4). In addition, the variant was also identified in the following databases: BRCA Exchange (Not Yet Reviewed), ClinVar (2x benign, 8x likely benign, 4x uncertain significance) and LOVD (2x likely benign, 6x uncertain significance). Based on the currently available information, c.2123C>A is classified as a benign variant according to ClinGen-BRCA1 Guidelines version v1.0.0. -

May 06, 2025

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1+BS3+BP4 -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:2Benign:2

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 02, 2024

BRCAlab, Lund University

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 03, 2009

Sharing Clinical Reports Project (SCRP)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 01, 2023

Department of Medical and Surgical Sciences, University of Bologna

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PP4(Supporting)+BS1(Strong)+BS3(Strong)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -

not provided

Uncertain:2

Mar 03, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Also known as 2242C>A; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12531920, 15385441, 16267036, 26689913, 27062684, 31131967, 20858050, 28529006, 31409081, 32546644, 32377563, 15343273, 29884841, 35402282) -

Oct 06, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Apr 24, 2022

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.2123C>A (p.Ser708Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251170 control chromosomes, predominantly at a frequency of 0.00039 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (6.8e-05 vs 0.001), allowing no conclusion about variant significance. c.2123C>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (example, Judkins_2005, Coulet_2010, Azzollini_2016). At-least one report of this variant co-occurring with a pathogenic variant (c.2062C>T, p.Gln688*) in the PTCH1 gene as an alternate molecular basis of disease in an individual with Gorlin syndrome has been reported (Paulo_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least two publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein had comparable homology-directed repair (HDR) activity to the wild type (Lu_2015) and a neutral impact in homologous recombination repair complementation assays (Bouwman_2020). Seven ClinVar submissons from clinical diagnostic laboratories (evaluation after 2014) cites the variant four times as uncertain significance and thrice as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

BRCA1-related disorder

Benign:1

Sep 28, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary breast ovarian cancer syndrome

Benign:1

Dec 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fanconi anemia, complementation group S

Benign:1

Oct 21, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

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

0.070

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.26

CADD

Benign

0.14

(source)

DANN

Benign

0.13

DEOGEN2

Benign

0.11

T;.;.;.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.81

T;T;T;T;T

M_CAP

Benign

0.052

MetaRNN

Benign

0.053

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.31

N;N;.;.;.

PhyloP100

-0.14

PrimateAI

Benign

0.25

PROVEAN

Benign

1.8

N;N;N;N;.

REVEL

Uncertain

0.47

Sift

Benign

1.0

T;T;T;T;.

Sift4G

Benign

1.0

T;T;T;T;.

Polyphen

0.0030

B;.;.;B;.

Vest4

0.24

MutPred

0.33

Loss of phosphorylation at S708 (P = 0.0675);Loss of phosphorylation at S708 (P = 0.0675);.;Loss of phosphorylation at S708 (P = 0.0675);.;

MVP

0.27

MPC

0.11

ClinPred

0.25

GERP RS

0.20

Varity_R

0.021

gMVP

0.066

Mutation Taster

=62/38

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over