17-43092388-C-T

Position:

chr17-43092388-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.3143G>A(p.Gly1048Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 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:8B:4

Conservation

PhyloP100: 0.151

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 Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13084206).

BP6

Variant 17-43092388-C-T is Benign according to our data. Variant chr17-43092388-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54776.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.3143G>A	p.Gly1048Asp	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.3143G>A	p.Gly1048Asp	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.0000239

AC:

AN:

251002

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135642

show subpopulations

Gnomad AFR exome

AF:

0.000369

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461658

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.000145

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:

0.0000658

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 05, 2023	This missense variant replaces glycine with aspartic acid at codon 1048 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in breast, pancreatic and prostate cancer case-control studies in 1 unaffected individual per study and absent in cancer cases (PMID: 30287823, 31214711, 32980694) and in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.1391 and 0.4042, respectively (PMID: 31131967). This variant has been identified in 9/282390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 06, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 26, 2021	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 18, 2022	This missense variant replaces glycine with aspartic acid at codon 1048 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in breast, pancreatic and prostate cancer case-control studies in 1 unaffected individual per study and absent in cancer cases (PMID: 30287823, 31214711, 32980694) and in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.1391 and 0.4042, respectively (PMID: 31131967). This variant has been identified in 9/282390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Aug 06, 2021	- -

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2023	Observed individuals undergoing clinical testing for hereditary breast and ovarian cancer (Judkins et al., 2005; Anczukow et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 3262G>A; This variant is associated with the following publications: (PMID: 26306726, 25011685, 15385441, 18273839, 9354803, 23893897, 9150149, 33087888, 30287823, 16267036, 31131967, 15343273, 35264596, 32980694) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 01, 2016	- -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.32

T;.;.;.

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.84

T;T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.2

L;L;.;.

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.3

D;D;D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.027

D;D;D;D

Sift4G

Benign

0.25

T;T;T;T

Polyphen

0.73

P;.;.;B

Vest4

0.41

MVP

0.54

MPC

0.22

ClinPred

0.034

GERP RS

-0.38

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

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