rs80357209

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_001407959.1(BRCA1):c.-152C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000682 in 1,613,388 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

BRCA1
NM_001407959.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:4O:1

Conservation

PhyloP100: 5.89

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 -1 ACMG points.

BP6

Variant 17-43104939-G-A is Benign according to our data. Variant chr17-43104939-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54529.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=9, not_provided=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.230C>T	p.Thr77Met	missense_variant	5/23	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.230C>T	p.Thr77Met	missense_variant	5/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251146

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461308

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726982

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:6Benign:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Sep 20, 2012	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 13, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 02, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 10, 2023	This missense variant replaces threonine with methionine at codon 77 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant does not impact BRCA1 function in a homology-directed repair and a haploid cell proliferation assay (PMID: 30209399, 30219179), and functional studies on ubiquitin-related activities also have reported partial to no impact (PMID: 16403807, 30696104). This variant has been reported in at least one individual each affected with breast, prostate and thyroid cancer (PMID: 22034289, 29684080, 31214711, 33471991; Leiden Open Variation Database DB-ID BRCA1_000065). This variant has been identified in 4/251146 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	curation	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Apr 12, 2024	Each variant was annotated with functional scores from MAVE data which was translated into functional evidence codes. All other evidence codes and combining criteria were adhered to as closely as possible based on the ClinGen VCEP (Variant Curation Expert Panel) gene-specific recommendations. See Supplemental Figure 34 of final paper (Supp Fig. 28 in preprint: doi:10.1101/2024.04.11.24305690) for a table to see which lines of evidence we did not have data for. The ClinGen VCEPs are highly regarded as the gold-standard for gene-specific variant curation and are developed after extensive evaluation of the evidence by clinical and scientific experts for the particular gene to classify genomic variants on a spectrum from pathogenic to benign using the 2015 ACMG/AMP Variant Interpretation Guidelines as a backbone (PMID: 25741868). Reclassification of these VUS variants from gnomAD or All of Us focused only on variants originally prescribed as VUS in ClinVar. To ensure reproducibility, transparency, and increased throughput, all the procedures for annotating variants and assigning evidence codes were codified using Python. All code has been made freely available and is linked in the Code Availability section and all reclassified variants with evidence codes used can be found in Tables S18-19 (preprint: doi:10.1101/2024.04.11.24305690). For the MAVE data, the clinical curation and clinical strength assignment as per the ClinGen recommendations in Brnich et al. (2020) (PMID: 31892348) for or against pathogenicity or benignity of each of these MAVE datasets utilized in this study were previously published in Fayer et al. (2021) (PMID: 34793697).In brief, for BRCA1 variants, if a variant was categorized as FUNC (functional), it was assigned BS3 evidence and no PS3 evidence, whereas if it was categorized as LOF (loss of function), the variant was assigned PS3 evidence and no BS3 evidence. Variants categorized as INT (intermediate) were left unannotated. For the BRCA1 combining criteria, greater than or equal to 1 criteria of strong benign evidence was enough to reclassify the VUS as Likely Benign. This variant GRCh38:17:43104939:G>A was assigned evidence codes ['BS3'] and an overall classification of Likely benign -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2021	Observed in individuals with breast cancer or thyroid cancer (Fackenthal 2012, Yehia 2018); Published functional studies demonstrate decreased E2 binding and E3 ligase activity, but no impact on BARD1 binding, HDR activity, or cell survival (Morris 2006, Findlay 2018, Starita 2018, Caleca 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek 2016); Also known as 349C>T; This variant is associated with the following publications: (PMID: 22034289, 29684080, 20104584, 24389207, 30219179, 30696104, 30209399, 29106415, 15385441, 20016594, 25823446, 16267036, 27720647, 24489791, 21309043, 26761715, 16403807) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 18, 2024	The BRCA1 c.230C>T (p.Thr77Met) variant has been reported in the published literature in individuals with breast cancer (PMID: 22034289 (2012), 16267036 (2005), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA1)), an individual with biliary tract cancer (PMID: 36243179 (2022)), and a reportedly healthy individual (PMID: 32467295 (2020)). Functional studies demonstrated that this variant has an inconclusive effect on protein function (PMID: 35659930 (2022), 30696104 (2019), 30209399 (2018), 26761715 (2016), 25823446 (2015), 21309043 (2011), 20016594 (2009), 16403807(2006)). The frequency of this variant in the general population, 0.000026 (3/113612 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 22, 2024	Variant summary: BRCA1 c.230C>T (p.Thr77Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251146 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.230C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer without strong evidence for pathogenicity (example: Fackenthal_2012; Judkins_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.4484G>T , p.Arg1495Met), providing supporting evidence for a benign role (BIC database). Multiple functional studies (including HDR assay assessement) have reported this variant as functional (example: Findlay_2018 and Clark_2022). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 15385441, 22034289, 24489791, 16403807, 21309043, 26761715, 20016594, 30209399, 30696104, 35659930). ClinVar contains an entry for this variant (Variation ID: 54529). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 06, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 21, 2023	This missense variant replaces threonine with methionine at codon 77 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant does not impact BRCA1 function in a homology-directed repair and a haploid cell proliferation assay (PMID: 30209399, 30219179), and functional studies on ubiquitin-related activities also have reported partial to no impact (PMID: 16403807, 30696104). This variant has been reported in at least one individual each affected with breast, prostate and thyroid cancer (PMID: 22034289, 29684080, 31214711, 33471991; Leiden Open Variation Database DB-ID BRCA1_000065). This variant has been identified in 4/251146 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jan 27, 2022

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

.;T;.;.;.;.;T;.;.;T;T;.;T;T;.;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.63

MetaRNN

Uncertain

0.59

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Uncertain

2.5

M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.62

N;N;N;N;N;N;N;N;N;.;N;N;N;D;D;.

REVEL

Uncertain

0.63

Sift

Benign

0.091

T;D;D;T;D;T;T;D;D;.;D;D;D;T;D;.

Sift4G

Uncertain

0.046

D;D;D;D;D;D;.;D;D;.;D;.;D;.;.;.

Polyphen

1.0, 1.0

.;D;.;.;.;D;.;.;D;.;.;.;.;.;.;.

Vest4

0.51

MutPred

0.30

Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);.;Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);.;Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);.;Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);.;.;

MVP

0.98

MPC

0.43

ClinPred

0.87

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.31

Position offset: 17

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