17-43092489-C-T

Position:

• chr17-43092489-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007294.4(BRCA1):​c.3042G>A​(p.Met1014Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: -0.116

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10349101).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.3042G>A	p.Met1014Ile	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	c.3042G>A	p.Met1014Ile	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 52

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

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	Ambry Genetics	Nov 23, 2024	The p.M1014I variant (also known as c.3042G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 3042. The methionine at codon 1014 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is poorly 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 03, 2016

Variant summary: The BRCA1 c.3042G>A (p.Met1014Ile) variant involves the alteration of a non-conserved nucleotide and results in a replacement of a medium size and hydrophobic Methionine (M) with a medium size and hydrophobic Isoleucine (I). 4/4 in silico tools predict a benign outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant is absent in 121268 control chromosomes. It has been reported in a tumor cell line, however, not reported in patients. Studies assessing the impact the variant may have on the function of BRCA1 were not published at the time of classification either. Due to the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2021

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. 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. This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 496363). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with isoleucine at codon 1014 of the BRCA1 protein (p.Met1014Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.0015	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	0.29
DANN	Benign	0.55
DEOGEN2	Benign	0.23	T;.;.;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.6	L;L;.;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.58	N;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.070	T;T;T;T
Sift4G	Benign	0.38	T;T;T;T
Polyphen		0.0010	B;.;.;B
Vest4		0.28
MutPred		0.40		Gain of catalytic residue at M1014 (P = 0.1547);Gain of catalytic residue at M1014 (P = 0.1547);.;Gain of catalytic residue at M1014 (P = 0.1547);
MVP		0.62
MPC		0.090
ClinPred		0.021	T
GERP RS		1.9
Varity_R		0.051
gMVP		0.20

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

Other links and lift over

dbSNP: rs1555588493; hg19: chr17-41244506; COSMIC: COSV58784316; COSMIC: COSV58784316;