17-43092758-T-G

Position:

chr17-43092758-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_007294.4(BRCA1):c.2773A>C(p.Ile925Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,614,112 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 Benign (★★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:13O:1

Conservation

PhyloP100: -0.281

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 Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022236645).

BP6

Variant 17-43092758-T-G is Benign according to our data. Variant chr17-43092758-T-G is described in ClinVar as [Benign]. Clinvar id is 37489.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092758-T-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.2773A>C	p.Ile925Leu	missense_variant	10/23	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.2773A>C	p.Ile925Leu	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000757

AC:

AN:

251016

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135660

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.0000289

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:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000217

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000625

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000666

Hom.:

Bravo

AF:

0.000264

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:13Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Counsyl	Apr 13, 2016	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00000326 -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jun 20, 2006	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 09, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as 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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 16, 2016	- -

not specified

Benign:2Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 23, 2020	Variant summary: BRCA1 c.2773A>C (p.Ile925Leu) 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 7.6e-05 in 251016 control chromosomes, predominantly at a frequency of 0.001 within the African or African-American 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 Syndrome (7.6e-05 vs 0.001), allowing no conclusion about variant significance. c.2773A>C has been reported in the literature in individuals affected with breast cancer and prostate cancer (example, Biunno_2014, Judkins_2005, Leongamornlert_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multifactorial probability models have reported a neutral outcome (example, Easton_2007, Lindor_2012). At-least one co-occurrence with another pathogenic variant has been observed in our laboratory (BRCA1 c.1386delG, p.Thr464fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 08, 2021

This variant is associated with the following publications: (PMID: 16518693, 22753008, 21990134, 18951461, 24853695, 24728327, 24729269, 17719744, 15235020, 17924331, 18951446, 23056176, 10923033, 22516946, 16267036, 25011685, 15385441) -

Malignant tumor of breast

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The p.Ile925Leu variant was identified in 2 of 40118 proband chromosomes (frequency: 0.0002) from individuals or families with Breast and Ovarian Cancer in a Sudanese and other populations (Abkevich 2004, Biunno 2014).The variant was identified by our laboratory in 1 individual with ovarian cancer. The variant was also identified in dbSNP (ID: rs rs4986847, with a minor allele frequency of 0.0002 (1000 Genomes Project); NHLBI Exome Sequencing Project (Exome Variant Server) in 4 of 4406 African Americans and 0 of 8600 European Americans; Exome Aggregation Consortium (ExAC) database in 12 of 10402 Africans and 1 of 11564 Latino, and not found in European (Non-Finnish),East Asian, South Asian, European (Finnish) or other populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also identified in HGMD, the ClinVar database (classified as a Likely Benign variant by the Sharing Clinical Reports Project, derived from Myriad reports; as likely Benign by GeneDX; as uncertain significance by BIC; as Benign by Ambry Genitics; ITMI and Invitae did not provide a classification). In the BIC database it was identified 4X with unknown clinical importance, and UMD (2X as an unknown variant). The p.Ile925 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. The p.Ile925Leu variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign. -

BRCA1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2019

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

Familial cancer of breast

Benign:1

Benign, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.27

CADD

Benign

0.91

DANN

Benign

0.89

DEOGEN2

Benign

0.14

T;.;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.095

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Benign

0.064

MetaRNN

Benign

0.022

T;T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.1

L;L;.;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.21

N;N;N;N

REVEL

Uncertain

0.34

Sift

Uncertain

0.0070

D;D;D;D

Sift4G

Benign

0.26

T;T;T;T

Polyphen

0.010

B;.;.;B

Vest4

0.33

MVP

0.36

MPC

0.088

ClinPred

0.0057

GERP RS

-2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.048

gMVP

0.055

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.

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