17-43094815-T-C

Position:

chr17-43094815-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_ModerateBP6_Very_Strong

The NM_007294.4(BRCA1):c.716A>G(p.His239Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H239L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:4B:6

Conservation

PhyloP100: -0.794

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 Benign. Variant got -8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.113386124).

BP6

Variant 17-43094815-T-C is Benign according to our data. Variant chr17-43094815-T-C is described in ClinVar as [Benign]. Clinvar id is 55677.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094815-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.716A>G	p.His239Arg	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.716A>G	p.His239Arg	missense_variant	10/23	1	NM_007294.4	P4	P38398-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000801

AC:

AN:

249838

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135308

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:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461476

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727044

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:4Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Benign:2

Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000925 -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2023	Observed in individuals with familial breast cancer, including one family where a deleterious BRCA1 variant was identified in other affected relatives who did not carry BRCA1 p.His239Arg (Dong et al., 1998; Arnold et al., 2002; Meindl et al., 2002); Published functional studies suggest no damaging effect: showed homologous recombination DNA repair activity and resistance to PARP inhibitors similar to wild type (Bouwman et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 835A>G; This variant is associated with the following publications: (PMID: 28277317, 15235020, 9010228, 9760198, 11802209, 12457999, 26206375, 16267036, 29884841, 9926942, 9582019, 9788437, 20215511, 31853058, 32377563, 31131967, 32546644) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 27, 2019	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 06, 2023	The p.H239R variant (also known as c.716A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 716. The histidine at codon 239 is replaced by arginine, an amino acid with highly similar properties. This alteration was reported in one German female with early-onset breast cancer and a family history of early-onset breast cancer; however, her other affected relatives were found to carry a BRCA1 pathogenic mutation (Dong J et al. Hum. Genet. 1998 Aug;103:154-61). This alteration was also reported in 1/989 German breast cancer or breast/ovarian cancer families undergoing BRCA1 gene testing (Meindl A et al. Int. J. Cancer. 2002 Feb;97:472-80). This variant was not detected among a German control cohort of 95 females and 25 males aged over 60 years without a family history of BRCA-associated cancers (Arnold N et al. J. Chromatogr. B Analyt. Technol. Biomed. Lif. 2002 Dec;782:99-104). This amino acid position is poorly conserved in available 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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 24, 2016	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Dec 15, 2022

Variant summary: BRCA1 c.716A>G (p.His239Arg) 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. The variant allele was found at a frequency of 8e-06 in 250078 control chromosomes (gnomAD and Arnold_2002). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.716A>G has been reported in the literature in affected individuals from families suspected of Hereditary Breast And Ovarian Cancer Syndrome without strong evidence (i.e. cosegregation data) for pathogenicity (e.g. Meindl_2002, Judkins_2005), including one case where another BRCA1 variant was identified in the other affected family members (Dong_1998). Thus, 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 (Bouwman_2020). These results showed no damaging effect of this variant on ability to complement BRCA1-deficient mouse embryonic stem cells in homologous recombination DNA repair (HRR) using cisplatin and olaparib sensitivity assays and a direct GFP HRR assay. Additionally, assessment by multifactorial likelihood analysis which incorporates research and clinical data, classified the variant as benign (Parsons_2019). Six submitters, including the expert panel ENIGMA, have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments: benign (n=2)/likely benign (n=1), VUS (n=3). Based on the evidence outlined above, the variant was classified as likely benign. -

BRCA1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.12

CADD

Benign

1.3

DANN

Benign

0.79

DEOGEN2

Benign

0.19

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

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.80

T;T;T;T;T;T;T;T;T;T;T;T;T;T

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.11

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.7

L;L;L;.;L;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.97

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

REVEL

Uncertain

0.60

Sift

Benign

0.10

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

Sift4G

Uncertain

0.029

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

Polyphen

0.25

B;.;.;.;B;.;B;.;.;B;.;.;.;.

Vest4

0.40

MutPred

0.10

Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);.;Gain of helix (P = 0.0496);.;.;.;.;Gain of helix (P = 0.0496);.;Gain of helix (P = 0.0496);.;Gain of helix (P = 0.0496);

MVP

0.85

MPC

0.26

ClinPred

0.15

GERP RS

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.036

gMVP

0.24

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