rs80357013

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM1BP4_ModerateBP6

The NM_007294.4(BRCA1):c.4261C>T(p.His1421Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. H1421R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 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:4B:11

Conservation

PhyloP100: 3.30

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Fanconi anemia, complementation group S
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
pancreatic cancer, susceptibility to, 4
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 28 uncertain in NM_007294.4

BP4

Computational evidence support a benign effect (MetaRNN=0.1792961).

BP6

Variant 17-43082500-G-A is Benign according to our data. Variant chr17-43082500-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 55156.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.4261C>T	p.His1421Tyr	missense_variant	Exon 12 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 link	c.4261C>T	p.His1421Tyr	missense_variant	Exon 12 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000955

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251434

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000137

AC:

AN:

1461832

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.000112

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1111960

Other (OTH)

AF:

0.0000497

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.000262

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.000955

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.567

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00000498

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:5

Feb 14, 2022

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Jun 04, 2024

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS3 + PM2 + BP4 -

Oct 24, 2022

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 19, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS3, BP4 c.4261C>T, located in exon 12 (exon 11 according to BIC nomenclature) of the BRCA1 gene, is predicted to result in the substitution of histidine by tyrosine at codon 1421, p.(His1421Tyr). This variant is found in 3/236896 alleles at a frequency of 0.001% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing and the BayesDel noAF score (-0.15) suggests that it does not affect the protein function (BP4). One calibrated study reported that it affects protein function similar to benign control variants (PMID:30765603) (BS3). This variant has been reported in the ClinVar database (3x uncertain significance, 1x benign, 7x likely benign), in the LOVD database (3x unclassified) and in BRCA Exchange database (unclassified). Based on currently available information, the variant c.4261C>T should be considered a likely benign variant according to ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA1 Version 1.0.0. -

Dec 16, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:2Benign:2

Sep 09, 2016

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Feb 03, 2010

Sharing Clinical Reports Project (SCRP)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 22, 2023

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 15, 1997

Breast Cancer Information Core (BIC) (BRCA1)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:2Benign:2

Jan 04, 2018

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 24, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26689913, 16267036, 21447777, 22682623, 17925560, 12080089, 9333265, 24845084, 18259752, 15689452, 28781887, 30400234, 30765603, 31131967, 15343273, 22737296, 19369211) -

Nov 23, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 30, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Apr 25, 2025

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BRCA1 c.4261C>T (p.His1421Tyr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 252434 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4261C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer or at high risk, without strong evidence for causality (examples, Shattuck-Eidens_1997, Dutil_2012, Vogel_2007, Judkins_2005, Diaz-Zabala_2018, Grant_2015, Ren_2021), it has also been reported in a control cohort (example, Dorling_2021). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant has been reported (Dutil_2012, pathogenic variant not provided) for this variant, supporting evidence for a benign role. Several functional experiments suggest that this variant has transcriptional and HDR activity similar to that of wild-type (Carvalho_2010, Hu_2002, Lu_2015, Woods_2016). The following publications have been ascertained in the context of this evaluation (PMID: 18992264, 30400234, 22682623, 30765603, 25479140, 12080089, 21447777, 16267036, 18259752, 26689913, 15385441, 15689452, 34196900, 9333265, 23704879, 17925560, 28781887). ClinVar contains an entry for this variant (Variation ID: 55156). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary breast ovarian cancer syndrome

Benign:1

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

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

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

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

M_CAP

Benign

0.058

MetaRNN

Benign

0.18

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

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.2

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

PhyloP100

3.3

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.9

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

REVEL

Benign

0.17

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.021

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

Polyphen

0.75, 0.98, 0.99

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

Vest4

0.45

MutPred

0.083

.;Gain of phosphorylation at H1421 (P = 0.0367);Gain of phosphorylation at H1421 (P = 0.0367);.;.;.;.;.;.;.;

MVP

0.59

MPC

0.43

ClinPred

0.68

GERP RS

4.5

Varity_R

0.10

gMVP

0.16

Mutation Taster

=75/25

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over