17-43093058-C-G

Position:

• chr17-43093058-C-G

Variant summary

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

The NM_007294.4(BRCA1):​c.2473G>C​(p.Asp825His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.754

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40192035).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.2473G>C	p.Asp825His	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.2473G>C	p.Asp825His	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250906 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135636

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461544 Hom.: 0 Cov.: 41 AF XY: 0.00000138 AC XY: 1 AN XY: 727092

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

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

May 01, 2024

The p.D825H variant (also known as c.2473G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 2473. The aspartic acid at codon 825 is replaced by histidine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D;.;.;.;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.81	T;T;T;T;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.40	T;T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.7	M;M;.;.;.
PrimateAI	Benign	0.23	T
PROVEAN	Pathogenic	-4.9	D;D;D;D;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.019	D;D;D;D;.
Sift4G	Uncertain	0.017	D;D;D;D;.
Polyphen		0.98	D;.;.;D;.
Vest4		0.37
MutPred		0.39		Gain of catalytic residue at R823 (P = 0.1033);Gain of catalytic residue at R823 (P = 0.1033);.;Gain of catalytic residue at R823 (P = 0.1033);.;
MVP		0.58
MPC		0.42
ClinPred		0.93	D
GERP RS		-0.43
Varity_R		0.087
gMVP		0.089

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: rs80357328; hg19: chr17-41245075;