rs55875643

Positions:

• chr13-32340065-C-G
• chr13-32340065-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000059.4(BRCA2):​c.5710C>G​(p.Leu1904Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:18
• Conservation: PhyloP100: 1.25

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0622077).
• BP6: Variant 13-32340065-C-G is Benign according to our data. Variant chr13-32340065-C-G is described in ClinVar as [Benign]. Clinvar id is 37990.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340065-C-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.5710C>G	p.Leu1904Val	missense_variant	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.5710C>G	p.Leu1904Val	missense_variant	11/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.5341C>G	p.Leu1781Val	missense_variant	11/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.5710C>G		non_coding_transcript_exon_variant	10/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000359 AC: 9 AN: 250772 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135624

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.0000290

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: 0.00000883

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461490 Hom.: 0 Cov.: 45 AF XY: 0.0000289 AC XY: 21 AN XY: 727044

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.000157

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: 0.00000989

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152274 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74464

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000262

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: 0.0000847 Hom.: 0

Bravo AF: 0.000253

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:18

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:6

Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
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 = 0.0000209 -
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) (BRCA2)	May 29, 2002	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Jan 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Dec 05, 2012	- -

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 22, 2016	Variant summary: The BRCA2 c.5710C>G (p.Leu1904Val) variant causes a missense change involving a non-conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 5/120788 (1/24160), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333. Multiple publications and databases cite the variant in affected individuals, in which multiple individuals carried another pathogenic BRCA2 variant (c.3922G>T (p.Glu1308X), c.1813dup (p.Ile605AsnfsX11)) and BRCA1 (c.5324T>G (p.Met1775Arg - classified as pathogenic by LCA) and c.1949_1950delTA (p.Ile650LysfsX22)). In addition, multiple reputable clinical laboratories classify the variant as "likely benign/benign." Therefore, the variant of interest has been classified as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21990134, 24055113, 22848303, 15744044, 24323938, 25637381, 26689913, 17924331, 28814288, 32926152) -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Leu1904Val variant was identified in 3 of 638 proband chromosomes (frequency: 0.005) from individuals or families with breast cancer and was not identified in 148 control chromosomes from healthy individuals (Fackenthal 2005, Zhou 2005, Diez 2011). The variant was also identified in dbSNP (ID: rs55875643) as "With Uncertain significance, other allele", ClinVar (classified as benign by ENIGMA, Counsyl, Invitae, Ambry Genetics, SCRP and one other clinical laboratory; as likely benign by GeneDx and four other clinical laboratories; and as uncertain significance by BIC), GeneInsight-COGR, MutDB, LOVD 3.0 (4x predicted neutral), UMD-LSDB (10x as likely neutral), BIC Database (8x with unknown significance), and ARUP Laboratories Database (not pathogenic or of no clinical significance). The variant was identified with the following co-occurring pathogenic variants: BRCA2 c.1813dup, p.Ile605Asnfs*11 (UMD database), BRCA1 c.1949_1950delTA, p.Ile650Lysfs*22 (Diez 2011), and BRCA2 c.7806-?_8632+?dup, p.Glu2878Glyfs*46 (our laboratory), increasing the likelihood that the p.Leu1904Val variant does not have clinical significance. The variant was not identified in Cosmic or the Zhejiang University database. The variant was identified in control databases in 14 of 276606 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 10 of 23996 chromosomes (freq: 0.0004), Other in 1 of 6450 chromosomes (freq: 0.0002), Latino in 1 of 34388 chromosomes (freq: 0.00003), and European in 2 of 126282 chromosomes (freq: 0.00002), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Leu1904 residue is not conserved in mammals and 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 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The information in the literature is conflicting and limited to in silico models (Easton 2007, Lindor 2012, Guidugli 2014, Zhou 2005). 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. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 08, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 30, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 18, 2022	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 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. -

Breast neoplasm Benign:1

Likely benign, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	0.40
DANN	Benign	0.39
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.065	N
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.062	T;T
MetaSVM	Benign	-0.98	T
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.020	N;N
REVEL	Uncertain	0.40
Sift	Benign	0.38	T;T
Sift4G	Benign	0.54	T;T
Vest4		0.69
MVP		0.75
MPC		0.021
ClinPred		0.037	T
GERP RS		3.3
gMVP		0.065

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: rs55875643; hg19: chr13-32914202;