17-43076501-G-C

Position:

• chr17-43076501-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007294.4(BRCA1):​c.4471C>G​(p.Pro1491Ala) 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 0.854

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06237644).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4471C>G	p.Pro1491Ala	missense_variant	13/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4471C>G	p.Pro1491Ala	missense_variant	13/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2024

The p.P1491A variant (also known as c.4471C>G), located in coding exon 12 of the BRCA1 gene, results from a C to G substitution at nucleotide position 4471. The proline at codon 1491 is replaced by alanine, an amino acid with highly similar properties. This variant was detected in 1/10 Italian male breast cancer patients (Miolo G et al. BMC Cancer, 2006 Jun;6:156). 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. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 20, 2022

ClinVar contains an entry for this variant (Variation ID: 55207). 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 is also known as c.4590C>G. This missense change has been observed in individual(s) with male breast cancer (PMID: 16764716). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1491 of the BRCA1 protein (p.Pro1491Ala). -

Familial cancer of breast Other:1

not provided, no classification provided

literature only

ClinVar Staff, National Center for Biotechnology Information (NCBI)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	12
DANN	Benign	0.70
DEOGEN2	Benign	0.15	.;T;.;.;.;.;.;T;.;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.84	T;D;T;T;D;T;D;D;D;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.062	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	.;L;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.4	D;N;.;D;N;D;D;N;D;N
REVEL	Benign	0.13
Sift	Benign	0.17	T;T;.;T;T;T;T;D;T;D
Sift4G	Benign	0.46	T;T;T;T;T;T;.;.;T;.
Polyphen		0.022, 0.42	.;B;.;.;.;.;.;B;.;.
Vest4		0.41
MVP		0.29
MPC		0.12
ClinPred		0.078	T
GERP RS		1.7
Varity_R		0.017
gMVP		0.10

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: rs111034213; hg19: chr17-41228518;