17-43047681-A-G

Position:

chr17-43047681-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate

The NM_007294.4(BRCA1):c.5429T>C(p.Val1810Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,134 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. V1810E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:1O:1

Conservation

PhyloP100: 3.36

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.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 17 uncertain in NM_007294.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.861

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.5429T>C	p.Val1810Ala	missense_variant	22/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.5429T>C	p.Val1810Ala	missense_variant	22/23	1	NM_007294.4	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00000398

AC:

AN:

251496

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00000342

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

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:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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

Bravo

AF:

0.0000264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:3Other:1

not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 11, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 10, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	This missense variant replaces valine with alanine at codon 1810 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). This variant has been reported to be functional in a haploid cell proliferation assay (PMID: 30209399). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251496 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. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2024	Observed in individuals undergoing multi-gene hereditary cancer panel testing (PMID: 31853058); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5548T>C; This variant is associated with the following publications: (PMID: 29884841, 32377563, 25348405, 30209399, 34981296, 31853058) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 25, 2017	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 23, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 18, 2022	This missense variant replaces valine with alanine at codon 1810 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). This variant has been reported to be functional in a haploid cell proliferation assay (PMID: 30209399). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251496 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 09, 2022

Variant summary: BRCA1 c.5429T>C (p.Val1810Ala) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251496 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5429T>C in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least one functional study reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant on homology directed repair (HDR) activity (e.g. Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign. -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The BRCA1 p.Val1810Ala variant was not identified in the literature, nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), HGMD, LOVD, COSMIC, GeneInsight COGR, or BIC. The p.Val1810Ala variant was identified in Clinvitae database (uncertain significance), the ClinVar database (classified as a uncertain significance by Ambry Genetics), and UMD (1X as a 3-unclassified variant). The p.Val1810 residue is conserved across mammals and other organisms, and four out of five computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Ala variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 unknown significance. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 17, 2023

Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 30209399). 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. ClinVar contains an entry for this variant (Variation ID: 185996). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1810 of the BRCA1 protein (p.Val1810Ala). This variant is present in population databases (rs80357451, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

.;T;.;T;T;T;.;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.90

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

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.86

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

MetaSVM

Pathogenic

0.80

MutationTaster

Benign

0.96

D;D;D;D;D;D;D;D;D;D;D;D;N;N

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.6

D;N;N;.;.;.;N;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0030

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.52, 0.84

.;P;.;.;.;P;.;.

Vest4

0.64

MVP

0.96

MPC

0.23

ClinPred

0.87

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.26

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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