chr17-43045739-A-C

Position:

chr17-43045739-A-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP6_Very_Strong

The NM_007294.4(BRCA1):c.5531T>G(p.Leu1844Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,724 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1844H) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:6B:8O:2

Conservation

PhyloP100: 2.24

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 Likely_benign. Variant got -6 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 17 uncertain in NM_007294.4

BP6

Variant 17-43045739-A-C is Benign according to our data. Variant chr17-43045739-A-C is described in ClinVar as [Benign]. Clinvar id is 55615.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43045739-A-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.5531T>G	p.Leu1844Arg	missense_variant	23/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.5531T>G	p.Leu1844Arg	missense_variant	23/23	1	NM_007294.4	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250824

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135504

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000299

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:

0.00000821

AC:

AN:

1461658

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000731

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:6Benign:8Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Benign:2Other:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 02, 2016	- -
not provided, no classification provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	-	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
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 = 0.000321 -

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2018	This variant is denoted BRCA1 c.5531T>G at the cDNA level, p.Leu1844Arg (L1844R) at the protein level, and results in the change of a Leucine to an Arginine (CTC>CGC). This variant, also known as BRCA1 5650T>G using alternate nomenclature, was reported as having an uncertain clinical effect based on biochemical and cell-based transcriptional assays (Lee 2010). This variant has been observed in at least one HBOC family and at least one individual with breast cancer (Peixoto 2014, Dean 2015). BRCA1 Leu1844Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the BRCT2 domain and a region known to interact with multiple proteins (UniProt, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Leu1844Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 02, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 09, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 17, 2018	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 14, 2020	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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 26, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 29, 2021	- -

Hereditary breast ovarian cancer syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

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.Leu1844Arg variant was identified in 2 of 2340 proband chromosomes (frequency: 0.0009) from individuals or families with breast and ovarian cancer (Dean 2015, Peixoto 2015). The variant identified in dbSNP (rs80357323) as â€šÃ„Ãºwith uncertain significance alleleâ€šÃ„Ã¹, ClinVar (interpreted as "uncertain significance by Ambry Genetics and 7 others and â€šÃ„Ãºlikely benign" by SCRP), LOVD 3.0 (observed 3x) and UMD-LSDB (observed 2x). The variant was identified in control databases in 5 of 245,562 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 15,300 chromosomes (freq: 0.0001), Ashkenazi Jewish in 3 of 9820 chromosomes (freq: 0.0003), while the variant was not observed in the Other, Latino, European, East Asian, Finnish, and South Asian populations. The functional effect of the p.Leu1844Arg missense variant was assessed in a series of assays. Based on the nonconcordant results in binding, protease sensitivity and structural stability assays, the variant was classified as having an uncertain functional effect (Lee 2010). The p.Leu1844 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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 uncertain significance. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Mar 19, 2024

Variant summary: BRCA1 c.5531T>G (p.Leu1844Arg) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250824 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5531T>G has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Dean_2015, Peixoto_2014, Judkins_2005, Guindalini_2022, deOliveira_2022) and in an individual with Sebacious Carcinoma in whom a different somatic etiology, namely a somatic inactivation of MSH2 and MSH6 genes was reported (Wield_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Several publications report experimental evidence evaluating an impact on protein function by transcriptional activation assays (example, Lee_2010, Woods_2016, Fernandes_2019). These results have consistently demonstrated no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 24845084, 26543556, 30765603, 35264596, 16267036, 17305420, 20516115, 24916970, 30225334, 28781887, 35534704, Iversen et al). ClinVar contains an entry for this variant (Variation ID: 55615). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

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

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Benign

0.57

LIST_S2

Uncertain

0.93

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

M_CAP

Pathogenic

0.63

MetaRNN

Uncertain

0.71

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

MetaSVM

Uncertain

-0.097

MutationAssessor

Benign

1.9

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

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.9

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

REVEL

Pathogenic

0.69

Sift

Benign

0.39

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

Sift4G

Uncertain

0.047

D;D;D;D;T;T;D;T

Polyphen

1.0, 0.95

.;D;.;.;.;P;.;.

Vest4

0.54

MVP

0.85

MPC

0.54

ClinPred

0.39

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.44

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