17-43124048-C-G

Position:

• chr17-43124048-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_007294.4(BRCA1):​c.49G>C​(p.Ala17Pro) 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 Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1 O:1
• Conservation: PhyloP100: 3.52

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 4 ACMG points.

• PM1: In a helix (size 13) in uniprot entity BRCA1_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.49G>C	p.Ala17Pro	missense_variant	2/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.49G>C	p.Ala17Pro	missense_variant	2/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Other:1

Uncertain significance, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Feb 02, 2024	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	.;T;.;.;.;T;.;T;T;.;T;T;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	0.42	N;N;N;N;N;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.87	N;N;N;N;N;N;N;.;N;N;N;D;D;.
REVEL	Uncertain	0.64
Sift	Benign	0.044	D;D;D;D;D;D;D;.;D;D;D;D;T;.
Sift4G	Benign	0.11	T;D;D;T;T;.;D;.;D;.;D;.;.;.
Polyphen		1.0, 1.0	.;D;.;.;D;.;D;.;.;.;.;.;.;.
Vest4		0.75
MutPred		0.44		Gain of methylation at K20 (P = 0.0755);Gain of methylation at K20 (P = 0.0755);Gain of methylation at K20 (P = 0.0755);Gain of methylation at K20 (P = 0.0755);Gain of methylation at K20 (P = 0.0755);Gain of methylation at K20 (P = 0.0755);Gain of methylation at K20 (P = 0.0755);Gain of methylation at K20 (P = 0.0755);Gain of methylation at K20 (P = 0.0755);Gain of methylation at K20 (P = 0.0755);Gain of methylation at K20 (P = 0.0755);Gain of methylation at K20 (P = 0.0755);Gain of methylation at K20 (P = 0.0755);Gain of methylation at K20 (P = 0.0755);
MVP		0.94
MPC		0.37
ClinPred		0.89	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.83

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: rs1402064476; hg19: chr17-41276065;