rs41286290

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4BP6_Very_Strong

The NM_007294.4(BRCA1):c.1001C>T(p.Pro334Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000706 in 1,613,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:11

Conservation

PhyloP100: 0.973

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 -7 ACMG points.

PM1

In a region_of_interest Disordered (size 32) in uniprot entity BRCA1_HUMAN there are 17 pathogenic changes around while only 6 benign (74%) in NM_007294.4

BP4

Computational evidence support a benign effect (MetaRNN=0.26464015).

BP6

Variant 17-43094530-G-A is Benign according to our data. Variant chr17-43094530-G-A is described in ClinVar as [Benign]. Clinvar id is 54099.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094530-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.1001C>T	p.Pro334Leu	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 link	c.1001C>T	p.Pro334Leu	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251380

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135856

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000753

AC:

110

AN:

1461770

Hom.:

Cov.:

AF XY:

0.0000811

AC XY:

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000863

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152006

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74236

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Benign:3

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 = 0.000000271 -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Feb 21, 2017	- -
Benign, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 24, 2017	Variant summary: The BRCA1 c.1001C>T (p.Pro334Leu) variant involves the alteration of a non-conserved nucleotide and is predicted to be damaging by 3/5 in silico tools. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect binding of multiple ESE sites. Functional studies show the variant to not affect splicing (Anczukow_2008, Caux-Moncoutier_2009). This variant was found in 2/121404 control chromosomes from ExAC at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005); however, it could still be a rare polymorphism. The variant has been reported in multiple affected individuals via publications and databases, including co-occurrence with other BRCA1 pathogenic variants in other allele (in trans), 2120insA (Judkins_2005), c.66_67delAG (BIC), and an unspecified deleterious variant (Spearman_2008), strongly supporting for benign outcome. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as benign. Taken together, this variant is classified as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2021	This variant is associated with the following publications: (PMID: 17924331, 19471317, 21990134, 18824701, 22753008, 18273839, 16267036, 23893897, 25348012, 18703817, 22045683) -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 22, 2019	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	Oct 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 13, 2016	- -

BRCA1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 2020

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). -

Hereditary breast ovarian cancer syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Uncertain

0.52

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

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.057

LIST_S2

Uncertain

0.91

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

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.26

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

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.5

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

PrimateAI

Benign

0.24

PROVEAN

Pathogenic

-7.4

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

REVEL

Uncertain

0.45

Sift

Benign

0.040

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

Sift4G

Benign

0.061

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

Polyphen

0.58

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

Vest4

0.37

MVP

0.78

MPC

0.11

ClinPred

0.061

GERP RS

1.9

Varity_R

0.085

gMVP

0.14

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