rs80357049

chr17-43092449-G-Achr17-43092449-G-Cchr17-43092449-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_007294.4(BRCA1):c.3082C>T(p.Arg1028Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1028H) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:8
• Conservation: PhyloP100: 1.68

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17178887).
• BP6: Variant 17-43092449-G-A is Benign according to our data. Variant chr17-43092449-G-A is described in ClinVar as [Benign]. Clinvar id is 37506.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092449-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.3082C>T	p.Arg1028Cys	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.3082C>T	p.Arg1028Cys	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151942 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251110 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135718

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: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000335 AC: 49 AN: 1461676 Hom.: 0 Cov.: 49 AF XY: 0.0000275 AC XY: 20 AN XY: 727136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151942 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74196

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Uncertain:3 Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -
Benign, reviewed by expert panel	curation	ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	Oct 10, 2023	The c.3082C>T variant in BRCA1 is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 1028 (p.Arg1028Cys). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.01, score threshold < 0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 32546644) (BS3 met). This variant has been observed in one individual with features considered inconsistent with an FA-associated phenotype, variant is homozygous (total score 1 point) (BS2_Supporting met; PMID: 29435075). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.0009 (based on Cosegregation LR=0.131; Pathology LR=0.056; Co-occurrence LR= 1.527; Family History LR= 0.081), below the thresholds for very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: 31131967). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP1_Strong, BS3, BS2_Supporting, BP5_Very strong). -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 20, 2019	Variant summary: BRCA1 c.3082C>T (p.Arg1028Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251110 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3082C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Klemp_2000, Coulet_2010, Azzollini_2016, Schenkel_2016) and endometrioid cancer (Garcia-Sanz_2016) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. The variant has also been found as a homozygous variant in a patient with a history of chronic lymphatic leukemia and breast cancer, but who did not exhibit symptoms typical of Fanconi anemia, as would be expected in a homozygous patient if the variant were pathogenic (Bondavalli_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as likley benign (n=4) and uncertain significance (n=1) . Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 16, 2021	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 28, 2019	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	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 24, 2017	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 01, 2018

This variant is associated with the following publications: (PMID: 12531920, 15385441, 16518693, 27376475, 10923033, 25782689, 10882858, 27062684, 29435075, 33087888) -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.085
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.34	N;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;N;N;N;N;N;N
PrimateAI	Benign	0.17	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Uncertain	0.34
Sift	Benign	0.11	T;T;T;T
Sift4G	Uncertain	0.051	T;T;T;D
Polyphen		0.59	P;.;.;B
Vest4		0.23
MutPred		0.40		Loss of MoRF binding (P = 0.0041);Loss of MoRF binding (P = 0.0041);.;Loss of MoRF binding (P = 0.0041);
MVP		0.68
MPC		0.27
ClinPred		0.37	T
GERP RS		5.1
Varity_R		0.13
gMVP		0.16

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: rs80357049; hg19: chr17-41244466; COSMIC: COSV58788564; COSMIC: COSV58788564;