rs80358777

chr13-32339909-G-Achr13-32339909-G-Cchr13-32339909-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000059.4(BRCA2):c.5554G>A(p.Val1852Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000224 in 1,608,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict 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. V1852D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:7
• Conservation: PhyloP100: 1.36

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18718863).
• BP6: Variant 13-32339909-G-A is Benign according to our data. Variant chr13-32339909-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37973.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=5}. Variant chr13-32339909-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.5554G>A	p.Val1852Ile	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.5554G>A	p.Val1852Ile	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152100 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

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: 0.0000404 AC: 10 AN: 247780 Hom.: 0 AF XY: 0.0000298 AC XY: 4 AN XY: 134038

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000591

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: 0.0000711

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000227 AC: 33 AN: 1456346 Hom.: 0 Cov.: 44 AF XY: 0.0000166 AC XY: 12 AN XY: 723878

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000908

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000379

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152100 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74280

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000109 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 30, 2023	The BRCA2 c.5554G>A (p.Val1852Ile) missense change has a maximum subpopulation frequency of 0.007% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in an individual with a personal history of breast cancer (PMID: 30287823). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Apr 18, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 29, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 09, 2023	The BRCA2 c.5554G>A; p.Val1852Ile variant (rs80358777) is reported in the literature in several individuals affected with breast cancer, as well as several healthy controls (Kim 2021, Momozawa 2018). This variant is also reported in ClinVar (Variation ID: 37973). It is observed in the non-Finnish European population with an overall allele frequency of 0.007% (9/127900 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.335). A multifactorial likelihood analysis based on family history, co-segregation and co-occurrence with pathogenic variants suggests that the p.Val1852Ile variant is unlikely to cause disease (Parsons 2019). Due to limited information, the clinical significance of the p.Val1852Ile variant is uncertain at this time. References: Kim JH et al. Analysis of BRCA1/2 variants of unknown significance in the prospective Korean Hereditary Breast Cancer study. Sci Rep. 2021 Apr 19;11(1):8485. PMID: 33875706. Parsons MT et al. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. Hum Mutat. 2019 Sep;40(9):1557-1578. PMID: 31131967. Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. PMID: 30287823. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 07, 2023	In the published literature, the variant has been reported in individuals with breast cancer (PMID: 33875706 (2021), 33471991 (2021), 30287823 (2018)), pancreatic cancer (PMID: 32980694 (2020)), and prostate cancer (PMID: 23555315 (2013)). The variant has also been identified in unaffected individuals (PMID: 33471991 (2021), 32980694 (2020), 30287823 (2018), 23555315 (2013)). The frequency of this variant in the general population, 0.00007 (9/127900 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 23, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2019	This variant is associated with the following publications: (PMID: 25348012, 23555315, 10923033, 29416916, 29467240, 21520333, 30287823, 31131967) -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 08, 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	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 31, 2016	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 15, 2021	- -
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 specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 07, 2023

Variant summary: BRCA2 c.5554G>A (p.Val1852Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 295242 control chromosomes (gnomAD and Momozawa_2018). This frequency is lower than the estimated maximum expected for a pathogenic (MPAF) variant in BRCA2 causing Hereditary Breast and Ovarian Cancer Syndrome (0.00075). In addition, the variant was also reported in some East Asian subpopulations with an even higher allele frequency, e.g. in the Japanese, with an allele frequency of 0.000388 (in the jMorp database), although this frequency is also somewhat lower than the MPAF, allowing no clear conclusions about variant significance. c.5554G>A has been reported in the literature in individuals affected with breast- and/or ovarian cancer (e.g. Momozawa_2018, Dorling_2021, Lee_2018, Kim_2020, Kim_2021), and other cancers (Haiman_2013, Dame_2018), as well as in healthy controls (Momozawa_2018, Dorling_2021). Co-occurrences with other pathogenic variants have been reported (BRCA2 c.9076C>T / p.Gln3026X in LOVD, and BRCA1 c.5467+1G>A in two internal LCA samples), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A large scale study utilizing multifactorial probability model for quantitative analysis of BRCA1 and BRCA2 variants predicted this variant to be likely benign (Parsons_2019). Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and multiple laboratories reported the variant with conflicting assessments (VUS, n = 5; likely benign, n = 4). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	2.1
Dann	Benign	0.68
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.60	D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.74	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.23	T;T
Sift4G	Benign	0.33	T;T
Vest4		0.17
MutPred		0.63		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.69
MPC		0.020
ClinPred		0.054	T
GERP RS		2.5
gMVP		0.12

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: rs80358777; hg19: chr13-32914046;