17-43106499-C-T

Position:

• chr17-43106499-C-T

Variant summary

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

The NM_007294.4(BRCA1):​c.169G>A​(p.Gly57Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,258 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38

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 zinc_finger_region RING-type (size 41) in uniprot entity BRCA1_HUMAN there are 65 pathogenic changes around while only 6 benign (92%) 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.169G>A	p.Gly57Arg	missense_variant	4/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.169G>A	p.Gly57Arg	missense_variant	4/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452258 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 722848

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

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

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

Oct 09, 2024

The p.G57R variant (also known as c.169G>A), located in coding exon 3 of the BRCA1 gene, results from a G to A substitution at nucleotide position 169. The glycine at codon 57 is replaced by arginine, an amino acid with dissimilar properties. This variant was detected in a cohort of 348 women diagnosed with breast cancer who had family history of breast and/or ovarian cancer (Palomba G et al. BMC Cancer, 2009 Jul;9:245). This variant was also found to prevent the interaction between the BRCA1 protein and the E2 ubiquitin conjugating enzyme UbcH5a (Morris JR et al. Hum. Mol. Genet., 2006 Feb;15:599-606), however one functional study suggests that this variant is functionally normal (Starita LM et al. Am J Hum Genet. 2018 Oct;103(4):498-508). Additional evidence is needed to confirm these findings. This amino acid position is 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	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	.;T;.;.;.;.;T;.;.;T;T;T;T;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	0.46	N;N;N;N;.;N;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.45	N;N;N;N;N;N;N;N;N;.;N;N;D;.
REVEL	Uncertain	0.61
Sift	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;.;D;D;D;.
Sift4G	Uncertain	0.027	D;D;D;T;D;T;.;D;D;.;D;D;.;.
Polyphen		1.0, 1.0, 1.0	.;D;.;.;.;D;.;.;D;.;.;.;.;.
Vest4		0.52
MutPred		0.51		Gain of solvent accessibility (P = 0.0014);Gain of solvent accessibility (P = 0.0014);Gain of solvent accessibility (P = 0.0014);Gain of solvent accessibility (P = 0.0014);.;Gain of solvent accessibility (P = 0.0014);Gain of solvent accessibility (P = 0.0014);.;Gain of solvent accessibility (P = 0.0014);Gain of solvent accessibility (P = 0.0014);Gain of solvent accessibility (P = 0.0014);Gain of solvent accessibility (P = 0.0014);Gain of solvent accessibility (P = 0.0014);.;
MVP		0.92
MPC		0.48
ClinPred		0.92	D
GERP RS		5.2
Varity_R		0.50
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs879255289; hg19: chr17-41258516;