17-43092947-T-C

Position:

• chr17-43092947-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_007294.4(BRCA1):​c.2584A>G​(p.Lys862Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,700 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K862N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:16
• Conservation: PhyloP100: 2.71

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 -8 ACMG points.

• BP6: Variant 17-43092947-T-C is Benign according to our data. Variant chr17-43092947-T-C is described in ClinVar as [Benign]. Clinvar id is 37476.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092947-T-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.2584A>G	p.Lys862Glu	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.2584A>G	p.Lys862Glu	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152222 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251066 Hom.: 0 AF XY: 0.0000590 AC XY: 8 AN XY: 135700

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000931

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000417 AC: 61 AN: 1461478 Hom.: 0 Cov.: 42 AF XY: 0.0000399 AC XY: 29 AN XY: 727028

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000376

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000719 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:16

Revision: reviewed by expert panel

Submissions by phenotype

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

Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Feb 10, 2010	- -
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 = 0.00000991 -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2019	This variant is associated with the following publications: (PMID: 21990134, 16518693, 22753008, 17924331, 26306726, 16267036, 23893897, 18273839, 25682074, 18951461, 18779604, 15385441, 25348012, 29453630) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2021	The BRCA1 c.2584A>G; p.Lys862Glu variant (rs80356927) is reported in the literature in individuals affected with breast and/or ovarian cancer, although it was no demonstrated to be disease-causing (Peyrat 1998). This variant is reported as benign or likely benign by multiple laboratories in ClinVar (Variation ID: 37476), and it is found in the general population with an overall allele frequency of 0.01% (16/282472 alleles) in the Genome Aggregation Database. The lysine at codon 862 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.808). However, multifactorial likelihood analysis considering family history of disease, co-occurrence with pathogenic variants, and co-segregation with disease suggest this variant has very low odds of causing disease (Easton 2007, Lindor 2012). However, given the lack of clinical and functional data, the significance of the p.Lys862Glu variant is uncertain at this time. References: Easton DF et al. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet. 2007 Nov;81(5):873-83. PMID: 17924331. Lindor NM et al. A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). Hum Mutat. 2012 Jan;33(1):8-21. PMID: 21990134 Peyrat JP et al. Germline BRCA1 mutations in patients from 84 families with breast and/or ovarian cancers in northern France. Eur J Cancer Prev. 1998 Feb;7 Suppl 1:S7-12. PMID: 10866029. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 19, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 13, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 26, 2019	Variant summary: BRCA1 c.2584A>G (p.Lys862Glu) results in a 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 6e-05 in 251066 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (6e-05 vs 0.001), allowing no conclusion about variant significance. c.2584A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, however these reports do not provide evidence for pathogenicity (Judkins_2005, Wong-Brown_2015, Anczukow_2008, Kurian_2008, Minucci_2015, Peyrat_1998, Li_2018, Kraemer_2019). In addition, multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be neutral (Easton 2007 and Lindor 2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other submitters, including one expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign while the expert panel has classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

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	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 25, 2015	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 22, 2021	- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 09, 2021

- -

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.Lys862Glu variant was identified in 8 of 111260 proband chromosomes (frequency: 0.00007) from individuals or families with breast cancer (Judkins 2005). The variant was also identified in dbSNP (ID: rs80356927) as “With Likely benign allele”, Clinvitae database (classified as benign by ClinVar; classified as likely benign by ClinVar, Invitae), Fanconi Anemia Mutation Database (LOVD), ARUP Laboratories BRCA Mutations Database (classified as not pathogenic or of no clinical significance), the ClinVar database (classified as benign by ENIGMA, Ambry genetics, SCRP; classified as likely benign by Invitae, GeneDx; classified as uncertain significance by BIC), the BIC database (5x with unknown clinical importance), and UMD (12x with a “likely neutral” classification). This variant was identified in the Exome Aggregation Consortium database (August 8th 2016) in 12 of 121328 chromosomes (freq. 0.0001) in the following populations: European in 8 of 66696 chromosomes (freq. 0.0001), Asian in 3 of 16502 chromosomes (freq. 0.0002), Finnish in 1 of 6614 chromosomes (freq. 0.0002), but was not seen in African, Latino and Other populations. The p.Lys862 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was also classified as neutral with odds in favor of neutrality 2059 in a study utilizing evidence of co-occurrence with a pathogenic variant, family history and if available segregation of the variant with disease (Easton 2007). The variant was also found to have a probability of being deleterious of 9.91×10−6 in a similar study (Lindor 2012). In addition, a study by Burk-Herrick (2005) found the variant has no effect by analyzing 19 marsupials and 94 eutherian mammal sequences, which were used to rank oncogenic risk of missence mutations based on conservation. 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 likely benign. -

BRCA1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.68	D;D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.2	M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.2	N;N;N;N
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Benign	0.34	T;T;T;T
Polyphen		0.97	D;.;.;P
Vest4		0.48
MVP		0.88
MPC		0.41
ClinPred		0.33	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.27
gMVP		0.20

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: rs80356927; hg19: chr17-41244964;