17-43092163-T-A

Position:

• chr17-43092163-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM2 PP3_Strong BP6

The NM_007294.4(BRCA1):​c.3368A>T​(p.Asp1123Val) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.20

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• BP6: Variant 17-43092163-T-A is Benign according to our data. Variant chr17-43092163-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 531304.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.3368A>T	p.Asp1123Val	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.3368A>T	p.Asp1123Val	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 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 11, 2024	The p.D1123V variant (also known as c.3368A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 3368. The aspartic acid at codon 1123 is replaced by valine, an amino acid with highly dissimilar 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 04, 2019

Variant summary: BRCA1 c.3368A>T (p.Asp1123Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250340 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3368A>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 29, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with BRCA1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with valine at codon 1123 of the BRCA1 protein (p.Asp1123Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;.;.;.
Eigen	Benign	0.069
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.8	M;M;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-7.4	D;D;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D
Polyphen		0.98	D;.;.;D
Vest4		0.70
MutPred		0.75		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);.;Gain of sheet (P = 0.0266);
MVP		0.78
MPC		0.44
ClinPred		0.96	D
GERP RS		4.0
Varity_R		0.24
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1555587851; hg19: chr17-41244180;