rs794727800

Positions:

• chr17-43104124-A-C
• chr17-43104124-A-G
• chr17-43104124-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007294.4(BRCA1):​c.439T>G​(p.Leu147Val) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L147F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Scores: Splicing: ADA: 0.005745
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.37

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34681988).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.439T>G	p.Leu147Val	missense_variant, splice_region_variant	6/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.439T>G	p.Leu147Val	missense_variant, splice_region_variant	6/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

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

Dec 20, 2019

The p.L147V variant (also known as c.439T>G), located in coding exon 5 of the BRCA1 gene, results from a T to G substitution at nucleotide position 439. The leucine at codon 147 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 10, 2023

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 147 of the BRCA1 protein (p.Leu147Val). 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: 230275). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 25823446). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;T;T;D;D;D;D;D;D;D;T
M_CAP	Pathogenic	0.67	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.2	M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.84	N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0090	D;T;T;T;T;T;T;T;T;T;T;.;T;T;T;T
Sift4G	Benign	0.42	T;T;D;T;T;T;.;.;T;.;D;.;D;.;D;.
Polyphen		0.92, 0.99, 1.0, 0.92	.;P;.;.;.;D;.;D;.;.;P;.;.;.;.;.
Vest4		0.35
MutPred		0.12		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);.;Gain of helix (P = 0.0696);.;Gain of helix (P = 0.0696);.;.;Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);.;Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP		0.95
MPC		0.23
ClinPred		0.66	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0057
dbscSNV1_RF	Benign	0.36
SpliceAI score (max)		0.090		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: rs794727800; hg19: chr17-41256141;