rs879255482

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6

The NM_007294.4(BRCA1):c.3048T>G(p.Asn1016Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:2

Conservation

PhyloP100: -0.207

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 17-43092483-A-C is Benign according to our data. Variant chr17-43092483-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252871.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.3048T>G	p.Asn1016Lys	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.3048T>G	p.Asn1016Lys	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1461682

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727130

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 19, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Dec 05, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 09, 2024	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 07, 2022	This missense variant replaces asparagine with lysine at codon 1016 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 not been reported in individuals affected with BRCA1-related disorders in the literature. This variant has not been identified 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	Ambry Genetics	Mar 15, 2024	The p.N1016K variant (also known as c.3048T>G), located in coding exon 9 of the BRCA1 gene, results from a T to G substitution at nucleotide position 3048. The asparagine at codon 1016 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
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). -

Hereditary breast ovarian cancer syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 20, 2022	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1016 of the BRCA1 protein (p.Asn1016Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 252871). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jun 24, 2021	The BRCA1 c.3048T>G (p.Asn1016Lys) missense change is absent in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/ ). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional studies. This variant is absent in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, BP4. -

BRCA1-related cancer predisposition

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Aug 13, 2024

This missense variant replaces asparagine with lysine at codon 1016 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA1-related disorders in the literature. This variant has not been identified 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Apr 10, 2024

The BRCA1 c.3048T>G (p.Asn1016Lys) variant has been reported in the published literature to be located in a region of the BRCA1 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)) and predicted to have a neutral functional impact (PMID: 32377563 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

0.0045

BayesDel_noAF

Benign

-0.23

CADD

Benign

1.6

DANN

Benign

0.71

DEOGEN2

Uncertain

0.62

D;.;.;.

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.83

T;T;T;T

M_CAP

Pathogenic

0.53

MetaRNN

Uncertain

0.48

T;T;T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Uncertain

2.3

M;M;.;.

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.7

D;D;D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.0060

D;D;D;D

Sift4G

Uncertain

0.012

D;D;D;D

Polyphen

0.70

P;.;.;P

Vest4

0.52

MutPred

0.36

Gain of methylation at N1016 (P = 0.0024);Gain of methylation at N1016 (P = 0.0024);.;Gain of methylation at N1016 (P = 0.0024);

MVP

0.44

MPC

0.31

ClinPred

0.83

GERP RS

-4.2

Varity_R

0.17

gMVP

0.16

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