rs80356867

chr17-43092164-C-Achr17-43092164-C-Gchr17-43092164-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP3_Moderate BP6

The NM_007294.4(BRCA1):c.3367G>T(p.Asp1123Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1123V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:3
• Conservation: PhyloP100: 0.903

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899
• BP6: Variant 17-43092164-C-A is Benign according to our data. Variant chr17-43092164-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54860.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.3367G>T	p.Asp1123Tyr	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.3367G>T	p.Asp1123Tyr	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250340 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135508

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461102 Hom.: 0 Cov.: 39 AF XY: 0.00000275 AC XY: 2 AN XY: 726894

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:4 Benign:1

Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 13, 2012	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 18, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 26, 2023	This missense variant replaces aspartic acid with tyrosine at codon 1123 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 18092194, 25777348). This variant has also been identified in 2/250340 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 06, 2022	The p.D1123Y variant (also known as c.3367G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 3367. The aspartic acid at codon 1123 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been identified in multiple individuals who have a personal and/or family history that is suggestive of HBOC (Seymour IJ et al. Breast Cancer Res. Treat. 2008 Nov;112:343-9; El Saghir NS et al. Oncologist. 2015 Apr;20:357-64; Fanale D et al. Front Oncol. 2021 Jun;11:682445). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 28, 2023	This missense variant replaces aspartic acid with tyrosine at codon 1123 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least three individuals affected with breast cancer (PMID: 25777348, 34178674). This variant has been identified in 2/250340 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
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). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 07, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 3486G>T; Observed in individuals with personal and/or family history of breast and/or ovarian cancer (Seymour et al., 2008; El Saghir et al., 2015; Abu-Helalah et al., 2020; Fanale et al., 2021; Abdel-Razeq et al., 2022); This variant is associated with the following publications: (PMID: 25777348, 18092194, 15385441, 21523855, 33376347, 29884841, 32377563, 33067490, 10923033, 35402282, 34178674) -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 05, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.12
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.63	D;.;.;.
Eigen	Benign	0.086
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	0.089	D
MutationAssessor	Uncertain	2.5	M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-7.3	D;D;D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.98	D;.;.;D
Vest4		0.78
MutPred		0.65		Loss of disorder (P = 0.0334);Loss of disorder (P = 0.0334);.;Loss of disorder (P = 0.0334);
MVP		0.81
MPC		0.39
ClinPred		0.97	D
GERP RS		4.1
Varity_R		0.37
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs80356867; hg19: chr17-41244181; COSMIC: COSV58788991; COSMIC: COSV58788991;