17-43094148-A-T

Position:

chr17-43094148-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PP3_ModerateBP6_Very_Strong

The NM_007294.4(BRCA1):c.1383T>A(p.Phe461Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,932 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 Benign (★★★).

Frequency

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

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:7B:1

Conservation

PhyloP100: 1.84

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:

BRCA1 (HGNC:):

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

BP6

Variant 17-43094148-A-T is Benign according to our data. Variant chr17-43094148-A-T is described in ClinVar as [Benign]. Clinvar id is 54228.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.1383T>A	p.Phe461Leu	missense_variant	10/23	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.1383T>A	p.Phe461Leu	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461730

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727172

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:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Benign

Submissions summary: Uncertain:7Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 06, 2023	The p.F461L variant (also known as c.1383T>A), located in coding exon 9 of the BRCA1 gene, results from a T to A substitution at nucleotide position 1383. The phenylalanine at codon 461 is replaced by leucine, an amino acid with highly similar properties. This alteration has also been identified in an early-onset familial breast cancer kindred (Katagiri T, J. Hum. Genet. 1998; 43(1):42-8), another family with breast and/or ovarian cancer (Lu W et al. Fam Cancer, 2012 Sep;11:381-5), and a patient with prostate cancer (Pugh TJ et al. Clin Cancer Res, 2009 Aug;15:5008-16). 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 16, 2023	This missense variant replaces phenylalanine with leucine at codon 461 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two families suspected of hereditary breast and/or ovarian cancer (PMID: 9609997, 22476429) and in an individual affected with prostate cancer (PMID: 19638463). A multifactorial analysis has reported likelihood ratios for pathogenicity based on segregation, co-occurrence with a pathogenic variant and family history of 0.0048, 1.256 and 1.9867, respectively (PMID: 31131967). This variant has been identified in 1/31410 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. -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Benign:1

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 = 0.000244 -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Nov 25, 2004	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 17, 2024

Variant summary: BRCA1 c.1383T>A (p.Phe461Leu) results in a non-conservative amino acid change located in the BRCA1, serine-rich domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251048 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1383T>A has been reported in the literature as a VUS in individuals affected with Hereditary Breast And Ovarian Cancer (e.g., Lu_2012, Judkins_2005, Katagiri_1998). However, these report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as benign (CAGI class 1) in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019). An expert panel has also deemed a classification as benign citing a multifactorial likelihood quantitative analysis (Parsons_2019). The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 22476429, 31112341, 9609997, 31131967). ClinVar contains an entry for this variant (Variation ID: 54228). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 23, 2022

Observed in individuals with a personal or family history of breast, prostate and other cancers and identified in an individual who had BRCA1/2 testing (Katagiri et al., 1999; Judkins et al., 2005; Pugh et al., 2009; Lu et al., 2012); 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 1502T>A; This variant is associated with the following publications: (PMID: 9609997, 22476429, 16267036, 15343273, 31131967, 19638463, 15235020, 12531920, 16518693, 15385441, 25637381) -

BRCA1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 2024

The BRCA1 c.1383T>A variant is predicted to result in the amino acid substitution p.Phe461Leu. This variant was identified in at least one individual who underwent clinical testing for hereditary breast and ovarian cancer (HBOC; Judkins et al. 2005. PubMed ID: 16267036). A different sequence variant resulting in the same amino acid substitution (c.1381C>T, p.Phe461Leu) has been reported in patients with breast cancer and gastric cancer, and has also been reported as a variant of uncertain significance (Katagiri et al. 1998. PubMed ID: 9609997; Amendola et al. 2015. PubMed ID: 25637381, supplemental). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/54228/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 461 of the BRCA1 protein (p.Phe461Leu). This variant is present in population databases (rs56046357, gnomAD 0.007%). This missense change has been observed in individual(s) with breast, ovarian, prostate and gastric cancer (PMID: 9609997, 19638463, 22476429). ClinVar contains an entry for this variant (Variation ID: 54228). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a low probability of being pathogenic (PMID: 31131967). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

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

Eigen

Uncertain

0.39

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.94

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

H;H;.;.;.;.;.;.;.

MutationTaster

Benign

0.87

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

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.9

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

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

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

Sift4G

Benign

0.085

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

Polyphen

1.0

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

Vest4

0.68

MutPred

0.79

Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);.;Gain of helix (P = 0.0034);.;Gain of helix (P = 0.0034);.;.;Gain of helix (P = 0.0034);

MVP

0.99

MPC

0.49

ClinPred

0.98

GERP RS

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.70

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