chr17-43094773-G-T

Position:

• chr17-43094773-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_007294.4(BRCA1):​c.758C>A​(p.Ala253Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,792 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.972

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24047846).
• BP6: Variant 17-43094773-G-T is Benign according to our data. Variant chr17-43094773-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1759651.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.758C>A	p.Ala253Glu	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.758C>A	p.Ala253Glu	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459792 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 31, 2021	The p.A253E variant (also known as c.758C>A), located in coding exon 9 of the BRCA1 gene, results from a C to A substitution at nucleotide position 758. The alanine at codon 253 is replaced by glutamic acid, an amino acid with dissimilar properties. This amino acid position is conserved. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.;.;.;.;.;T;.;T;.;T;T;.;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.83	T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.5	M;M;M;.;M;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.86	N;N;N;N;N;N;N;N;N;N;.;N;N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D;D;T;D;T;D;D;D;D;D;.;D;D;D
Sift4G	Uncertain	0.012	D;D;T;D;T;.;.;T;.;D;.;D;.;D
Polyphen		1.0	D;.;.;.;D;.;D;.;.;B;.;.;.;.
Vest4		0.39
MutPred		0.14		Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);.;Loss of helix (P = 0.079);.;.;.;.;Loss of helix (P = 0.079);.;Loss of helix (P = 0.079);.;Loss of helix (P = 0.079);
MVP		0.86
MPC		0.22
ClinPred		0.47	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-41246790;