13-32337301-A-G

Position:

• chr13-32337301-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000059.4(BRCA2):​c.2946A>G​(p.Ile982Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,612,682 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:8
• Conservation: PhyloP100: -0.225

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028999805).
• BP6: Variant 13-32337301-A-G is Benign according to our data. Variant chr13-32337301-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37810.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=2}. Variant chr13-32337301-A-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.2946A>G	p.Ile982Met	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.2946A>G	p.Ile982Met	missense_variant	11/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.2577A>G	p.Ile859Met	missense_variant	11/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.2946A>G		non_coding_transcript_exon_variant	10/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000884 AC: 22 AN: 248848 Hom.: 0 AF XY: 0.0000816 AC XY: 11 AN XY: 134852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000584

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1460364 Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14 AN XY: 726412

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000540

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74490

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000642

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Feb 19, 2014	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Jun 20, 2002	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

Hereditary cancer-predisposing syndrome Benign:3

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). -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 22, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 22, 2020	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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 19, 2021	Variant summary: BRCA2 c.2946A>G (p.Ile982Met) 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 8.8e-05 in 248848 control chromosomes, predominantly at a frequency of 0.00058 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (8.8e-05 vs 0.00075), allowing no conclusion about variant significance. c.2946A>G has been reported in the literature in case and control cohorts in studies of individuals with breast, colorectal and esophageal squamous cell cancer with no significant reported association (example, Lee_2008, Dong_2018, Fujita_2020, Ko_2020, Momozawa_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant have been reported (Dong_2018, BRCA1 c.141C>A, p.Cys47*), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3; VUS, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the absence of evidence supporting an actionable outcome in literature spanning over 12 years of evolution, no reported association with breast and colorectal cancer (Momozawa_2018, Fujita_2020), and the emerging consensus supporting a likely benign outcome among peers as outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 22, 2021	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 27, 2023

Observed in individuals with breast, ovarian or colorectal cancer and also in unaffected controls (Lee et al., 2008; Dong et al., 2018; Momozawa et al., 2018; Zhang et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 3174A>G; This variant is associated with the following publications: (PMID: 23929434, 34917121, 32467295, 33309985, 30039884, 30287823, 18284688, 32566972, 31396961, 26295337, 32114502, 36243179, 35918668) -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Ile982Met variant was identified in 1 of 17,146 proband chromosomes (frequency: 0.00006) from individuals or families with breast cancer and was present in 5 of 47,462 control chromosomes (frequency: 0.0001) from healthy individuals (Momozawa 2018, Lee 2008). The variant was identified in dbSNP (rs80358541) as “with likely benign, other allele”, ClinVar (interpreted as "uncertain significance" by Ambry Genetics and 4 others and "likely benign" by Invitae and 2 others) and LOVD 3.0 (observed 2x). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 21 of 244,312 chromosomes at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 20 of 33,344 chromosomes (freq: 0.0006), East Asian in 1 of 17,176 chromosomes (freq: 0.00006), but not in the African, Other, European, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Ile982 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Familial cancer of breast Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Center for Precision Medicine, Meizhou People's Hospital

-

- -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.9
DANN	Benign	0.87
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.040	N
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.029	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.2	N;N
REVEL	Benign	0.11
Sift	Benign	0.079	T;T
Sift4G	Benign	0.22	T;T
Vest4		0.26
MutPred		0.27		Gain of catalytic residue at I982 (P = 0.0044);Gain of catalytic residue at I982 (P = 0.0044);
MVP		0.59
MPC		0.071
ClinPred		0.032	T
GERP RS		-1.2
gMVP		0.17

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: rs80358541; hg19: chr13-32911438;