17-43093408-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:12

Conservation

PhyloP100: -0.143
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1
In a modified_residue Phosphoserine (size 0) in uniprot entity BRCA1_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_007294.4
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 id is 37447.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA1NM_007294.4 linkc.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
BRCA1ENST00000357654.9 linkc.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:
5
AN:
152126
Hom.:
0
Cov.:
32
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
GnomAD3 exomes
AF:
0.0000677
AC:
17
AN:
251170
Hom.:
0
AF XY:
0.0000810
AC XY:
11
AN XY:
135762
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:
0.000392
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000383
AC:
56
AN:
1461790
Hom.:
0
Cov.:
41
AF XY:
0.0000591
AC XY:
43
AN XY:
727192
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:
0.000406
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000153
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152126
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74302
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.000479
Bravo
AF:
0.0000151
ExAC
AF:
0.0000741
AC:
9

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:12
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:5
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. -

Nov 15, 2016
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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. -

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). -

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:2
Apr 03, 2009
Sharing Clinical Reports Project (SCRP)
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

- -

May 29, 2002
Breast Cancer Information Core (BIC) (BRCA1)
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
Oct 06, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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) -

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
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
0.14
DANN
Benign
0.13
DEOGEN2
Benign
0.11
T;.;.;.;T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.013
N
LIST_S2
Benign
0.81
T;T;T;T;T
M_CAP
Benign
0.052
D
MetaRNN
Benign
0.053
T;T;T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.31
N;N;.;.;.
PrimateAI
Benign
0.25
T
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
T
GERP RS
0.20
Varity_R
0.021
gMVP
0.066

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.

Other links and lift over

dbSNP: rs80357182; hg19: chr17-41245425; API