chr17-43094147-C-T

Position:

chr17-43094147-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_007294.4(BRCA1):c.1384G>A(p.Gly462Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G462E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:1

Conservation

PhyloP100: 3.35

Variant links:

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.1384G>A	p.Gly462Arg	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.1384G>A	p.Gly462Arg	missense_variant	10/23	1	NM_007294.4	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251048

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135686

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461726

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727162

show subpopulations

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:

0.0000171

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Alfa

AF:

0.0000956

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Sep 15, 1997	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Apr 21, 2009	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 14, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 03, 2023	This missense variant replaces glycine with arginine at codon 462 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study reported that this variant has a modest impact on BRCA1 function in a homology-directed repair assay (PMID: 26689913). This variant has been detected in a breast cancer case-control meta-analysis in 3/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000146) and in an individual affected with lung cancer (PMID: 26689913). This variant has been identified in 3/251048 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 08, 2023	The p.G462R variant (also known as c.1384G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 1384. The glycine at codon 462 is replaced by arginine, an amino acid with dissimilar properties. This alteration was described as a pathogenic mutation in a French study; however, data contributing to this classification was not provided (Coulet F et al. Genet Test Mol Biomarkers. 2010; 14:677-90). This alteration was not found to have an impact on splicing using a BRCA1 minigene and RT-PCR assay (Anczukow O et al. Genes Chromosomes Cancer. 2008 May;47(5):418-26). In a functional study this alteration was shown to retain 85% of homology-directed repair activity relative to wild type (Lu C et al. Nat Commun, 2015 Dec;6:10086). This alteration was also identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	Mar 21, 2023	This missense variant replaces glycine with arginine at codon 462 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study reported that this variant has a modest impact on BRCA1 function in a homology-directed repair assay (PMID: 26689913). This variant has been detected in a breast cancer case-control meta-analysis in 3/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000146) and in an individual affected with lung cancer (PMID: 26689913). This variant has been identified in 3/251048 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
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). -

Hereditary breast ovarian cancer syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 462 of the BRCA1 protein (p.Gly462Arg). This variant is present in population databases (rs80357221, gnomAD 0.007%). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 34326862, 34855882). ClinVar contains an entry for this variant (Variation ID: 54230). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 26689913). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Oct 11, 2021	The BRCA1 c.1384G>A (p.Gly462Arg) missense change has a maximum subpopulation frequency of 0.0026% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/17-41246164-C-T?dataset=gnomad_r2_1). Seven of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), however in vitro functional studies have shown that this variant results in ~85% of homology-directed repair (HDR) activity of the BRCA1 protein compared to wild-type (PMID: 26689913). This variant has been reported in individuals with urothelial carcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, and skin cutaneous melanoma (PMID: 29625052). In addition, two individuals with this variant are reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES database https://whi.color.com/variant/17-41246164-C-T). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3, BS3. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 21, 2023

Variant summary: BRCA1 c.1384G>A (p.Gly462Arg) results in a non-conservative amino acid change located in the BRCA1, serine-rich domain (IPR025994) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251048 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1384G>A has been reported in the literature in individuals affected with breast and/or ovarian cancer (e.g. Anczukow_2008, Coulet_2010). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant resulted in 85%-90% of normal homology directed repair (HDR) activity (Lu_2015). In addition, a multifactorial model including cosegregation data from affected families predicted this variant to be benign (Caputo_2021). Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 24, 2023

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive: reduced, but not absent, homology-directed repair activity (Lu et al., 2015); Multifactorial analysis suggests that this variant is benign (Caputo et al., 2021); Observed in individuals with melanoma, bladder or lung cancer (Lu et al., 2015; Huang et al., 2018; Yehia et al., 2018); Also known as 1503G>A; This variant is associated with the following publications: (PMID: 18273839, 15385441, 20858050, 16518693, 15001988, 12531920, 25637381, 23704879, 23893897, 29684080, 29625052, 26689913, 34597585, 15343273) -

BRCA1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2023

The BRCA1 c.1384G>A variant is predicted to result in the amino acid substitution p.Gly462Arg. This variant has been reported in individuals with breast/ovarian cancer, bladder urothelial carcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, skin cutaneous melanoma, Cowden/Cowden-like and Bannayan-Riley-Ruvalcaba syndromes (BRRS) (Anczuków et al. 2008. PubMed ID: 18273839. Table S1; Coulet et al. 2010. PubMed ID: 20858050; Lu et al. 2015. PubMed ID: 26689913. Table S12; Huang et al. 2018. PubMed ID: 29625052. Table S2B; Yehia et al. 2018. PubMed ID: 29684080. Table S9). Functional studies showed that this variant does not have an impact on splicing using a BRCA1 minigene and RT-PCR assay (Anczuków et al. 2008. PubMed ID: 18273839. Table S1) and retains 85% of wild type repair function (Lu et al. 2015. PubMed ID: 26689913. Table S22). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-41246164-C-T). In ClinVar, this variant has conflicting interpretations, including likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/54230/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.48

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.63

D;.;.;.;T;T;.;.;T

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

M;M;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-7.8

D;D;D;D;.;D;D;D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0060

D;D;D;D;.;D;D;D;D

Sift4G

Uncertain

0.0090

D;D;D;D;.;D;.;D;D

Polyphen

1.0

D;.;.;D;.;.;.;.;.

Vest4

0.66

MutPred

0.76

Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);.;Gain of solvent accessibility (P = 0.0055);.;Gain of solvent accessibility (P = 0.0055);.;.;Gain of solvent accessibility (P = 0.0055);

MVP

0.97

MPC

0.50

ClinPred

0.97

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Varity_R

0.68

gMVP

0.43

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

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