rs786201916

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_000059.4(BRCA2):c.316G>A(p.Gly106Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense, splice_region

Scores

Splicing: ADA: 0.9977

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 1.35

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant 13-32319325-G-A is Pathogenic according to our data. Variant chr13-32319325-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 185084.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.316G>A	p.Gly106Arg	missense_variant, splice_region_variant	Exon 3 of 27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.316G>A	p.Gly106Arg	missense_variant, splice_region_variant	Exon 3 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.-54G>A		splice_region_variant	Exon 3 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000530893 link	c.-54G>A		5_prime_UTR_variant	Exon 3 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.316G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249688

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135388

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1458908

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725898

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fanconi anemia

Pathogenic:1

Nov 18, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.316G>A (p.Gly106Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. As the variant alters the last conserved nucleotide of exon 3, adjacent to the canonical splice donor site, several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 5' splicing donor site. One predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing demonstrating a partial level of out of frame exon 3 skipping in >60% of transcripts (Tubeuf_2020). The variant allele was found at a frequency of 4e-06 in 249688 control chromosomes. c.316G>A has been reported in the literature as a maternally inherited allele in a compound heterozygous genotype in at-least one individual affected with Fanconi Anemia (example, Radulovic_2023 cited in Tubeuf_2020). A maternal family history of breast cancer was reported although the extent of genotyping was not provided (Tubeuf_2020). The following publications have been ascertained in the context of this evaluation (PMID: 36721989, 32641407, 27878467). ClinVar contains an entry for this variant (Variation ID: 185084). Based on the evidence outlined above, the variant was classified as likely pathogenic for autosomal recessive Fanconi Anemia and Autosomal Dominant Herediatry Breast and Ovarian Cancer (HBOC). -

Fanconi anemia complementation group D1

Pathogenic:1

Oct 05, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2, PM3 -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Jul 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 106 of the BRCA2 protein (p.Gly106Arg). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs786201916, gnomAD 0.003%). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 32641407, 36721989). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 185084). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 32641407). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 32641407). For these reasons, this variant has been classified as Pathogenic. -

not provided

Uncertain:1

May 01, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies are inconclusive: in vitro studies demonstrate partially aberrant splicing and partial rescue of cell survival, though the physiological relevance of a reduction (versus a complete loss) of BRCA2 is unknown (Tubeuf et al., 2020); Observed in individuals with Fanconi Anemia, including an individual with a pathogenic variant on the opposite allele (in trans) in published literature (Tubeuf et al., 2020; Radulovic et al., 2023); Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Yadav et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Also known as 544G>A; This variant is associated with the following publications: (PMID: 31911673, 29884841, 32377563, 36721989, 32641407, 27878467, 31853058) -

Hereditary cancer-predisposing syndrome

Uncertain:1

Dec 03, 2015

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G106R variant (also known as c.316G>A) located in coding exon 2 of the BRCA2 gene. This variant results from a G to A substitution at nucleotide position 316. The amino acid change results in glycine to arginine at codon 106, an amino acid with dissimilar properties. This change occurs in the last base pair of coding exon 2 which makes it likely to have some effect on normal mRNA splicing; however, predictions of potential splicing impact from two different computer models are conflicting. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 225000 alleles tested) in our clinical cohort (includes this individual). This amino acid position is well conserved in available vertebrate species, but this alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.G106R remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

0.11

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.78

M_CAP

Benign

0.035

MetaRNN

Benign

0.29

T;T

MetaSVM

Benign

-0.93

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.11

Sift

Benign

0.093

T;T

Sift4G

Benign

0.14

T;T

Vest4

0.41

MutPred

0.28

Gain of MoRF binding (P = 0.0166);Gain of MoRF binding (P = 0.0166);

MVP

0.91

MPC

0.077

ClinPred

0.46

GERP RS

3.3

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.88

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.29

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over