17-43047699-A-T

Position:

• chr17-43047699-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 8P and 8B. PVS1 BP6_Very_Strong

The ENST00000468300.5(BRCA1):​c.2025T>A​(p.Cys675Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,614,188 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 Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. C675C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: BRCA1 ENST00000468300.5 stop_gained
• Clinical Significance: Benign reviewed by expert panel U:2 B:14 O:2
• Conservation: PhyloP100: 0.527

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 0 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 66 pathogenic variants in the truncated region.
• BP6: Variant 17-43047699-A-T is Benign according to our data. Variant chr17-43047699-A-T is described in ClinVar as [Benign]. Clinvar id is 55568.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43047699-A-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5411T>A	p.Val1804Asp	missense_variant	22/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5411T>A	p.Val1804Asp	missense_variant	22/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000994 AC: 25 AN: 251482 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000616 AC: 90 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.000612

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74474

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.000276

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:14 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:3 Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000374 -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 01, 2011	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2020	This variant is associated with the following publications: (PMID: 24916970, 21990134, 12014998, 28758972, 17924331, 24728327, 15350310, 17308087, 15172985, 12955716, 16528612, 19770520, 20516115, 22753008, 14534301, 17305420, 21447777, 22505045, 21520273, 25637381, 25782689, 23867111, 27272900, 26764160, 26332594, 28781887, 30209399, 30765603, 26689913) -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 17, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	BRCA1: BP1 -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 03, 2022	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 27, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 02, 2015	- -

Hereditary breast ovarian cancer syndrome Benign:2

Likely benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 10, 2020	The p.Cys675X variant in BRCA1 is classified as likely benign because it has been identified in 0.048% (5/10370) of Ashkenazi Jewish and 0.047% (17/35440) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Additionally, variant is present as nonsense variant in 1 of 6 transcripts (not major transcript), while resulting in a missense variant in the remaining 5 transcripts. This variant was classified as Benign on August 10, 2015 by the ClinGen-approved Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel (Variation ID 55568). ACMG/AMP Criteria applied: BS1. -

Ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 p.Val1804Asp variant was identified in 2 of 1268 proband chromosomes (frequency: 0.002) from individuals with breast or ovarian cancer (Diez 2003), and was also identified in 2 of 2108 control chromosomes (frequency 0.001) from another study (Osorio 2007). This variant was reported in dbSNP (rs80356920) “with untested allele”, in LOVD, and in BIC 14X with unknown clinical importance. The p.Val1804Asp variant was also identified in UMD 6X as a neutral variant, where it was reported to have co-occurred with two different known BRCA1 pathogenic mutations (BRCA1 c.5266dup (p.Gln1756ProfsX74); BRCA1 c.2269delG (p.Val757PhefsX8)), increasing the likelihood that it is benign. The results of functional studies in the literature are somewhat conflicting, though most lean toward neutrality. Ostrow (2004) determined that the variant reduced transcriptional activity in a yeast-based assay, suggesting it may be deleterious; Carvalho (2007) found transcription activity comparable to wild type in yeast but reduced in mammalian cells, suggesting that it may represent a moderate-risk variant; while Lee (2010) found no functional impact of the variant on transcription. Two studies determined that the variant had no impact on protease sensitivity, and no destabilizing effect on the BRCT domain), suggesting that it is neutral (Lee 2010 20516115, Williams 2003 14534301. In addition, histopathology results provide evidence for neutrality, with loss of the variant allele in tumour tissue (Spearman 2008 18824701). Furthermore, the p.Val1804 residue is poorly conserved in mammals and lower organisms; computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein; and in silico structural or probability-based models suggest that this is a neutral variant (Capanu 2011, Easton 2007, Lindor 2012, Mirkovic 2004). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	15
DANN	Benign	0.97
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.021	N
MutationTaster	Benign	1.0	A;N;N;N;N;N;N;N;N;N;N;N;N;N
Vest4		0.77
ClinPred		0.059	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs80356920; hg19: chr17-41199716; COSMIC: COSV99070449;