17-43104139-G-C

Position:

• chr17-43104139-G-C

Variant summary

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

The ENST00000357654.9(BRCA1):​c.424C>G​(p.Pro142Ala) 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. 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. P142H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 ENST00000357654.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0560

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22985336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.424C>G	p.Pro142Ala	missense_variant	6/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.424C>G	p.Pro142Ala	missense_variant	6/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2014

The p.P142A variant (also known as c.424C>G and 543C>G), located in coding exon 5 of the BRCA1 gene, results from a C to G substitution at nucleotide position 424. The proline at codon 142 is replaced by alanine, an amino acid with highly similar properties. This variant was reported in a Lebanese breast cancer patient whose large family had many family members affected with breast and/or ovarian cancers (Jalkh N et al. Hered Cancer Clin Pract. 2012 Jun 19;10(1):7). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13,006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 42,000 alleles tested) in our clinical cohort (includes this individual). This amino acid position is moderately conserved in available vertebrate species. In addition, this alteration is predicted to be benign by PolyPhen but deleterious by SIFT in silico analyses. Since supporting evidence is limited at this time, the clinical significance of p.P142A remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	9.1
DANN	Benign	0.97
DEOGEN2	Benign	0.23	.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.4	M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.92	N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;D
REVEL	Uncertain	0.61
Sift	Benign	0.040	D;D;D;D;D;D;D;T;D;D;D;.;D;D;D;T
Sift4G	Benign	0.83	T;T;T;T;T;T;.;.;T;.;D;.;D;.;D;.
Polyphen		0.82, 1.0, 1.0, 0.85	.;P;.;.;.;D;.;D;.;.;P;.;.;.;.;.
Vest4		0.33
MutPred		0.26		Loss of glycosylation at P142 (P = 0.0155);Loss of glycosylation at P142 (P = 0.0155);Loss of glycosylation at P142 (P = 0.0155);Loss of glycosylation at P142 (P = 0.0155);.;Loss of glycosylation at P142 (P = 0.0155);.;Loss of glycosylation at P142 (P = 0.0155);.;.;Loss of glycosylation at P142 (P = 0.0155);Loss of glycosylation at P142 (P = 0.0155);Loss of glycosylation at P142 (P = 0.0155);.;Loss of glycosylation at P142 (P = 0.0155);Loss of glycosylation at P142 (P = 0.0155);
MVP		0.86
MPC		0.12
ClinPred		0.22	T
GERP RS		-0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.4
Varity_R		0.062
gMVP		0.32

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: rs397509156; hg19: chr17-41256156;