rs56119278

Positions:

Variant summary

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

The NM_007294.4(BRCA1):c.4691T>C(p.Leu1564Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,614,174 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 Benign (★★★).

Frequency

Genomes: 𝑓 0.00053 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:18O:1

Conservation

PhyloP100: 1.35

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:

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=0.047209352).

BP6

Variant 17-43071223-A-G is Benign according to our data. Variant chr17-43071223-A-G is described in ClinVar as [Benign]. Clinvar id is 55262.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43071223-A-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.4691T>C	p.Leu1564Pro	missense_variant	15/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.4691T>C	p.Leu1564Pro	missense_variant	15/23	1	NM_007294.4	ENSP00000350283	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.000539

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00198

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000163

AC:

AN:

250804

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

135654

show subpopulations

Gnomad AFR exome

AF:

0.00235

Gnomad AMR exome

AF:

0.0000578

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:

0.000163

GnomAD4 exome

AF:

0.0000602

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00242

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000525

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00192

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000941

Hom.:

Bravo

AF:

0.000695

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000123

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:18Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Benign:4

Benign, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	- -
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 = 0.000102 -

Hereditary cancer-predisposing syndrome

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 05, 2015	- -
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	curation	Sema4, Sema4	Nov 11, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 03, 2018	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 17, 2016	Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of a medium size and hydrophobic Leucine (L) with a medium size and hydrophobic Proline (P). 3/4 in silico tools predict the variant to be neutral. It was observed predominantly in the African subcohorts of the ExAC project at an allele frequency of 0.13% which slightly exceeds the maximal expected allele frequency of a disease causing BRCA1 allele (0.1%). It was reported in several HBOC spectrum patients however without strong evidence for pathogenicity. The variant was observed to co-occur with pathogenic/possibly pathogenic BRCA1 and BRCA2 variants such as BRCA1 p.C64Y; p.Lys1290Ter, p.Val738fs, c.824ins10 and BRCA2 p.Lys1872_Ile1874fs indicating neutrality. A benign impact is also supported by computational analysis that integrated multiple forms of genetic evidence for the variant of interest (Lindor_2012). Carvalho_2007 showed decreased transcriptional activity in yeast and mammalian cells; however, Hayes_2000 showed transcription activation of the variant is comparable to wild-type BRCA1 in yeast. In addition, multiple literature and reputable databases/clinical laboratories classify this variant as likely benign or benign. Considering all evidence, the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 15, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 11, 2019	- -

Hereditary breast ovarian cancer syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Nov 15, 2022	- -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 08, 2022

- -

Breast neoplasm

Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

BRCA1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2024

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Pathogenic

0.34

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.15

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

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.77

T;T;T;T;T;T;T;T;T;T

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.047

T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

1.9

.;L;.;.;.;.;.;.;.;.

MutationTaster

Benign

0.97

N;N;N;N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.4

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

REVEL

Uncertain

0.55

Sift

Benign

0.14

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

Sift4G

Benign

0.12

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

Polyphen

0.83, 0.27

.;P;.;.;.;.;.;.;B;.

Vest4

0.38

MVP

0.78

MPC

0.14

ClinPred

0.018

GERP RS

3.7

Varity_R

0.16

gMVP

0.36

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