17-43091696-C-T

Position:

chr17-43091696-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_007294.4(BRCA1):c.3835G>A(p.Ala1279Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000681 in 1,614,192 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:9

Conservation

PhyloP100: 0.332

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 Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15092948).

BP6

Variant 17-43091696-C-T is Benign according to our data. Variant chr17-43091696-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55020.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=2, Uncertain_significance=2}. Variant chr17-43091696-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.3835G>A	p.Ala1279Thr	missense_variant	10/23	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.3835G>A	p.Ala1279Thr	missense_variant	10/23	1	NM_007294.4	ENSP00000350283	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

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:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251144

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135704

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:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74482

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:

0.00

Alfa

AF:

0.0000312

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 23, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 27, 2019	- -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 2023	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 26, 2012	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Nov 25, 2004	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 10, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 31, 2019	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. -
Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2017

- -

Malignant tumor of breast

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The BRCA1 p.Ala1279Thr variant was not identified in the literature nor was it identified in the GeneInsight-COGR, COSMIC, MutDB, ARUP Laboratories, or Zhejiang Colon Cancer databases. The variant was identified in dbSNP (ID: rs80357036) as â€šÃ„ÃºWith Uncertain significance, other alleleâ€šÃ„Ã¹, ClinVar and Clinvitae (3x classified as uncertain significance by Invitae, Quest Diagnostics and BIC; 2x classified as likely benign by Ambry Genetics and GeneDx; 1x classified as benign by SCRP), LOVD 3.0 (5 entries classified as effect unknown or not classified), UMD-LSDB (2 entries, classification neutral, 1 entry with a co-occurring pathogenic variant), BIC Database (1 entry, clinical importance unknown) databases. The variant was identified in control databases in 4 of 245878 chromosomes at a frequency of 0.000016 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 4 of 111354 chromosomes (freq: 0.000036), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Ala1279Thr residue is not conserved in mammals; indeed a threonine residue is observed in Gorilla gorilla at this position. 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 variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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 likely benign. -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.17

T;.;.;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.68

T;T;T;T

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.15

T;T;T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.6

M;M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;N;N;N;N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.54

N;N;N;N

REVEL

Uncertain

0.55

Sift

Uncertain

0.025

D;D;D;D

Sift4G

Benign

0.21

T;T;T;T

Polyphen

0.031

B;.;.;P

Vest4

0.32

MVP

0.75

MPC

0.079

ClinPred

0.10

GERP RS

3.3

Varity_R

0.032

gMVP

0.15

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