rs80357217

chr17-43091686-T-Achr17-43091686-T-Cchr17-43091686-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4 BP6

The NM_007294.4(BRCA1):c.3845A>T(p.Glu1282Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,872 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1282G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:5
• Conservation: PhyloP100: 2.02

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36084023).
• BP6: Variant 17-43091686-T-A is Benign according to our data. Variant chr17-43091686-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55027.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=5}. Variant chr17-43091686-T-A is described in Lovd as [Benign]. Variant chr17-43091686-T-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.3845A>T	p.Glu1282Val	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.3845A>T	p.Glu1282Val	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251120 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135696

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: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727240

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: 0.0000153

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 16, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 07, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Dec 23, 2003	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 02, 2016	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 07, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 24, 2018	This alteration is classified as likely 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	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:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2021	Published functional studies demonstrate no damaging effect: restoration of proliferation in BRCA1-deficient mouse embryonic stem cells as well as lack of significant sensitivity to cisplatin exposure (Bouwman 2013); Not observed at significant frequency in large population cohorts (Lek 2016); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. RT-PCR analysis suggests the variant does not disrupt normal splicing (Wai 2020); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 3964A>T; This variant is associated with the following publications: (PMID: 16267036, 21523855, 22737296, 15343273, 32123317, 23867111) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2017	- -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 24, 2022

DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.3845A>T, in exon 10 that results in an amino acid change, p.Glu1282Val. This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.0004% (dbSNP rs80357217). The p.Glu1282Val change affects a moderately conserved amino acid residue located in a domain of the BRCA1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu1282Val substitution. Functional studies have indicated that this sequence change does not impact function of the BRCA1 protein (PMID: 23867111, 32123317). Due to insufficient evidences, the clinical significance of the p.Glu1282Val change remains unknown at this time. -

BRCA1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 2023

The BRCA1 c.3845A>T variant is predicted to result in the amino acid substitution p.Glu1282Val. This variant was listed as uncertain in one study of variant classification (Table 2, Judkins et al. 2005. PubMed ID: 16267036). RT-PCR analysis suggests this variant does not impact mRNA splicing (Table S1, Wai et al. 2020. PubMed ID: 32123317). This variant occurs within a region of the BRCA1 gene that is predicted to be tolerant to variation (Table 2, Dines et al. 2020. PubMed ID: 31911673). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-41243703-T-A). In ClinVar, this variant is interpreted as likely benign/uncertain (https://preview.ncbi.nlm.nih.gov/clinvar/variation/55027/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.;.;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.7	M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D
Polyphen		0.84	P;.;.;P
Vest4		0.54
MutPred		0.29		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);.;Gain of sheet (P = 0.0477);
MVP		0.87
MPC		0.47
ClinPred		0.87	D
GERP RS		5.2
Varity_R		0.16
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs80357217; hg19: chr17-41243703; COSMIC: COSV104621702; COSMIC: COSV104621702;