rs786203000

Positions:

• chr13-32398162-A-C
• chr13-32398162-A-G
• chr13-32398162-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000059.4(BRCA2):​c.9649A>C​(p.Met3217Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000619 in 1,454,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense, splice_region
• Scores: Splicing: ADA: 0.001482
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.686

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12696272).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9649A>C	p.Met3217Leu	missense_variant, splice_region_variant	27/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9649A>C	p.Met3217Leu	missense_variant, splice_region_variant	27/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.9280A>C	p.Met3094Leu	missense_variant, splice_region_variant	27/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1707A>C		splice_region_variant, non_coding_transcript_exon_variant	26/26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*1707A>C		3_prime_UTR_variant	26/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000619 AC: 9 AN: 1454076 Hom.: 0 Cov.: 31 AF XY: 0.00000553 AC XY: 4 AN XY: 723528

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000722

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 08, 2021	The p.M3217L variant (also known as c.9649A>C) is located in coding exon 26 of the BRCA2 gene. The methionine at codon 3217 is replaced by leucine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 26. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 08, 2019	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Aug 19, 2023

This variant has not been reported in individuals with BRCA2-related conditions in the published literature. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 10, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 186499). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3217 of the BRCA2 protein (p.Met3217Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	6.0
DANN	Benign	0.64
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.42	N
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.94	T
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.39	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.85	T;T
Sift4G	Benign	1.0	T;T
Vest4		0.28
MutPred		0.38		Gain of catalytic residue at M3217 (P = 8e-04);Gain of catalytic residue at M3217 (P = 8e-04);
MVP		0.72
MPC		0.020
ClinPred		0.027	T
GERP RS		-0.46
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0015
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.020		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: rs786203000; hg19: chr13-32972299;