rs56204128

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM5BP4_ModerateBP6

The NM_000059.4(BRCA2):c.9353T>C(p.Met3118Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 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. M3118I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:3

Conservation

PhyloP100: 0.250

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 1 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 14 uncertain in NM_000059.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-32394785-TG-TCTTGAT is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.118056536).

BP6

Variant 13-32394785-T-C is Benign according to our data. Variant chr13-32394785-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38232.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.9353T>C	p.Met3118Thr	missense_variant	25/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.9353T>C	p.Met3118Thr	missense_variant	25/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251326

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00

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:

0.00000205

AC:

AN:

1461798

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000333

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:3Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 18, 2011	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 23, 2022	The BRCA2 c.9353T>C (p.Met3118Thr) missense change has a maximum subpopulation frequency of 0.025% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been reported in an individual with a personal history of breast cancer and osteosarcoma and a family history of breast cancer (PMID: 9609997), however this individual did not undergo germline evaluation of other potential predisposing genes including TP53 (PMID: 11091690). It has also been reported in one individual in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. In summary, the evidence currently available is insufficient to determine the role of this variant in hereditary breast and ovarian cancer syndrome and/or Fanconi anemia. It has therefore been classified as of uncertain significance. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2023	Observed in individuals with personal and/or family history of breast cancer, including a patient who also harbored a pathogenic variant in PALB2 (Katagiri et al., 1998; Kuno et al., 1999; Dorling et al., 2021; Cheng et al., 2023); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 9581T>C; This variant is associated with the following publications: (PMID: 12491487, 24055113, 19043619, 25637381, 9609997, 31131967, 37002487, 12228710, 33471991, 23555315, 11091690) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 26, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 29, 2021	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 25, 2023	The p.M3118T variant (also known as c.9353T>C), located in coding exon 24 of the BRCA2 gene, results from a T to C substitution at nucleotide position 9353. The methionine at codon 3118 is replaced by threonine, an amino acid with similar properties. This alteration was reported in a Japanese breast cancer family (Katagiri T et al. J. Hum. Genet., 1998;43:42-8). It was also reported in a Japanese female diagnosed with osteosarcoma of the leg at age 16 and bilateral breast cancers at ages 32 and 34; her mother was diagnosed with breast cancer at age 45. This case report did not mention whether the patient had undergone TP53 germline testing (Kuno T et al. Breast Cancer, 1999 Jan;6:51-54). This alteration was detected in a cohort of 88 African American individuals with a personal and/or family history of breast and/or ovarian cancer (McDonald JT et al. PLoS One, 2022 Oct;17:e0273835). This alteration was also reported in a patient with breast cancer who was also found to carry a pathogenic mutation in the PALB2 gene (Cheng JM et al. Breast Cancer Res Treat, 2023 Jun;199:389-397). In one study, this variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Using a computational method that produces a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function, this alteration is predicted to be neutral (Karchin R et al. Cancer Inform, 2008 Apr;6:203-16). This amino acid position is not well conserved in available vertebrate species, and threonine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 24, 2016	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Apr 06, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 22, 2023

Variant summary: BRCA2 c.9353T>C (p.Met3118Thr) results in a non-conservative amino acid change located in the OB3 (oligonucleotide binding) fold (IPR015188) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251326 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant was also reported in 1/2559 African American women, over 70 years of age with no history of cancer (FLOSSIES database). c.9353T>C has been reported in the literature in individuals affected with breast cancer (Katagiri_1998, Dorling_2021, McDonald_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with one other pathogenic variant has been reported (BRCA1 c.2940delA [p.Pro981HisfsX19], BIC database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 33471991, 24055113, 23555315, 19043619, 9609997, 11091690, 36315513, 12491487). Eight ClinVar submitters have assessed the variant since 2014: six classified the variant as uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

BRCA2-related condition

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2024

The BRCA2 c.9353T>C variant is predicted to result in the amino acid substitution p.Met3118Thr. This variant was reported in an individual with breast cancer and osteosarcoma and a family history of breast cancer (Katagiri et al 1998. PubMed ID: 9609997). Of note, there was no mention of additional genetic testing beyond BRCA1 and BRCA2 analysis, for this family. A bioinformatics analysis utilizing protein likelihood ratios predicted that the p.Met3118 variant would have a neutral impact on protein function (Supplementary Table 1, Karchin R et al 2008. PubMed ID: 19043619). This variant was interpreted as a variant of uncertain significance in a study of incidental findings in participants’ exomes (Table S1, Dorschner et al 2013. PubMed ID: 24055113; Amendola et al 2015. PubMed ID: 25637381). This variant has been reported twice in the Breast Cancer Information Core database with uncertain clinical significance (https://research.nhgri.nih.gov/bic/). This variant is reported in 0.025% of alleles in individuals of African descent in gnomAD and has conflicting interpretations in the ClinVar database, ranging from likely benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/38232/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Breast neoplasm

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Uncertain

0.020

Cadd

Benign

0.50

Dann

Benign

0.50

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.021

M_CAP

Benign

0.049

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.94

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.80

N;N

REVEL

Uncertain

0.47

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Vest4

0.52

MVP

0.82

MPC

0.021

ClinPred

0.0074

GERP RS

-1.3

gMVP

0.23

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

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