rs80357250

Positions:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong

The NM_007294.4(BRCA1):c.2002C>T(p.Leu668Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:5B:16

Conservation

PhyloP100: 0.198

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15550563).

BP6

Variant 17-43093529-G-A is Benign according to our data. Variant chr17-43093529-G-A is described in ClinVar as [Benign]. Clinvar id is 37441.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093529-G-A 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.2002C>T	p.Leu668Phe	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.2002C>T	p.Leu668Phe	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251202

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

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:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000479

AC:

AN:

1461736

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000594

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000105

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:5Benign:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 06, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 28, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 04, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2020	This variant is associated with the following publications: (PMID: 24607278, 22753008, 28398198, 21990134, 24448499, 23867111, 24504028) -

not specified

Uncertain:1Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 22, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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 = 0.000194 -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Dec 15, 2008	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -

Hereditary cancer-predisposing syndrome

Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 02, 2017	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 09, 2020	- -

Hereditary breast ovarian cancer syndrome

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Aug 01, 2016	Found in a male patient having exome sequencing for an unrelated indication. No known personal or family history of breast cancer. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Breast and/or ovarian cancer

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Jun 14, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 16, 2022	- -

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.Leu668Phe variant was identified in 11 of 3508 proband chromosomes (frequency: 0.003) from individuals with breast or ovarian cancer and was identified in 3 of 2748 healthy control chromosomes (frequency: 0.001) from these studies (Cvok 2008, Diez 2003, Infante 2006, Osorio 2007, Shattuck-Eidens 1997). The variant was also reported in the following databases: dbSNP (ID: rs80357250) â€šÃ„ÃºWith non-pathogenic alleleâ€šÃ„Ã¹, UMD (2X as an unclassified variant), BIC (25X with unknown clinical importance), and LOVD. The p.Leu668 residue is conserved in mammals; however, computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact of the p.Leu668Phe variant to the protein and this information is not very predictive of pathogenicity. In silico studies have either predicted this variant as neutral or close to the neutral threshold (Abkevich 2004, Easton 2007, Lindor 2012, Tavtigian 2006) and Myriad classifies this variant as a polymorphism (personal communication). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.059

BayesDel_noAF

Benign

-0.15

CADD

Benign

7.6

DANN

Benign

0.95

DEOGEN2

Benign

0.34

T;.;.;.;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.056

LIST_S2

Uncertain

0.87

D;D;D;D;D

M_CAP

Benign

0.044

MetaRNN

Benign

0.16

T;T;T;T;T

MetaSVM

Benign

-0.29

MutationAssessor

Uncertain

2.1

M;M;.;.;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.0

N;N;N;N;.

REVEL

Uncertain

0.49

Sift

Benign

0.094

T;T;T;T;.

Sift4G

Uncertain

0.056

T;T;T;T;.

Polyphen

0.81

P;.;.;B;.

Vest4

0.37

MVP

0.90

MPC

0.11

ClinPred

0.054

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.034

gMVP

0.22

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