rs1060502353

Variant names:

• chr17-43115739-G-A
• rs1060502353
• NM_007294.4:c.121C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43115739-G-A
• chr17-43115739-G-C
• chr17-43115739-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):​c.121C>T​(p.His41Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H41R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 4.40

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a zinc_finger_region RING-type (size 41) in uniprot entity BRCA1_HUMAN there are 65 pathogenic changes around while only 6 benign (92%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43115738-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 17-43115739-G-A is Pathogenic according to our data. Variant chr17-43115739-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 580736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.121C>T	p.His41Tyr	missense_variant	Exon 3 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.121C>T	p.His41Tyr	missense_variant	Exon 3 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3 Other:1

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Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Aug 30, 2021

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 24, 2021

Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

May 05, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

BRCA1 (p.His41Tyr): This sequence change replaces histidine with tyrosine at codon 41 of the BRCA1 protein (p.His41Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (gnomAD exomes, gnomAD genomes). This variant has been observed in an individual affected with breast cancer (PMID: 28486781). ClinVar contains an entry for this variant (Variation ID: 580736). ClinVar classifies this variant as Pathogenic, rated 2 stars, with 4 submissions, 8 publications (15168169, 16403807, 20103620, 21725363, 23161852 and 3 more) and no conflicts. This variant has been reported to affect BRCA1 protein function (PMID: 25823446, 30209399). This variant disrupts the p.His41 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15168169, 24489791, 16403807, 23161852, 20103620, 21725363, 30209399). Therefore, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

May 29, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: impaired BARD1 binding and E3 auto-ubiquitination, and classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (PMID: 25823446, 30209399, 33087888); Observed in individuals with breast cancer (PMID: 32733560, 33067490, 28486781, 34597585, 37901051, 34290354); This variant was classified as pathogenic based on a multifactorial model incorporating family history, pathology, and co-segregation (PMID: 34597585); 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 c.240C>T; This variant is associated with the following publications: (PMID: 30209399, 32733560, 33067490, 33087888, 31131967, 25823446, 20104584, 24389207, 8944023, 34290354, 28486781, 34597585, 37901051) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jul 03, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H41Y pathogenic mutation (also known as c.121C>T), located in coding exon 2 of the BRCA1 gene, results from a C to T substitution at nucleotide position 121. The histidine at codon 41 is replaced by tyrosine, an amino acid with similar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Lolas Hamameh S et al. Int. J. Cancer, 2017 Aug;141:750-756; Abdel-Razeq H et al. J Oncol, 2020 Jul;2020:8362179). This alteration was shown to have severely defective E3 ubiquitin ligase activity, however it maintained intact BARD1 binding capability (Starita LM et al. Genetics, 2015 Jun;200:413-22). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). This variant affects a known zinc binding motif which is predicted to disrupt protein folding (Ambry internal data; Brzovic PS et al. Nat. Struct. Biol., 2001 Oct;8:833-7; Brzovic PS et al. Proc. Natl. Acad. Sci. U.S.A., 2003 May;100:5646-51). Two other alterations at the same codon, p.H41R (c.122A>G) and p.H41N (c.121C>A), have been shown to be functionally deleterious in multiple functional assays (Morris JR et al. Hum. Mol. Genet. 2006 Feb; 15(4):599-606; Ransburgh DJ et al. Cancer Res. 2010 Feb; 70(3):988-95; Towler WI et al. Hum. Mutat. 2013 Mar; 34(3):439-45; Caleca L et al. Cancers (Basel), 2019 Jan;11; Starita LM et al. Genetics, 2015 Jun;200:413-22; Starita LM et al. Am. J. Hum. Genet., 2018 Oct;103:498-508; Findlay GM et al. Nature, 2018 10;562:217-222). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

May 08, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces histidine with tyrosine at codon 41 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown the variant to cause loss of protein function in a haploid cell proliferation assay (PMID: 30209399), reduced E3 ligase activity (PMID: 25823446) and disrupted binding to E2 ubiquitin conjugating enzyme (PMID: 16403807). This variant has been reported in at least three individuals affected with breast cancer that are described as high-risk or have a family history of breast and ovarian cancer (PMID: 28486781, 32733560, 33067490). Other missense variants at this codon have been reported as (likely) disease-causing in ClinVar (variation ID: 54166, 868161, 230862, 409353), suggesting that the conserved histidine is functionally important. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Sep 14, 2020

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Data included in classification: This variant has been reported in one UK case of ovarain cancer, with LOH at 17q on tumour testing. The variant is absent from GNOMAD (PM2_sup), predicted deleterious on multiple in silico tools including REVEL 0.9 (PP3_sup), affects the same amino acid residue as c.122A>G p.(His41Arg) (PM5_mod), with this residue recognised by ENIGMA as of functional importance (PM1_mod). The variant is non-functional on saturation genome editing in haploid BRCA1 cellular model (Findlay et al 2018, PMID: 30209399) (PS3_Strong). Data not included in classification: Recent (2019-2020) classification as LP/P from Invitae and Color -

Aug 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 41 of the BRCA1 protein (p.His41Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 28486781). ClinVar contains an entry for this variant (Variation ID: 580736). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 25823446, 30209399). This variant disrupts the p.His41 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15168169, 16403807, 20103620, 21725363, 23161852, 24489791, 30209399). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

BRCA1-related cancer predisposition Pathogenic:1

Jul 29, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces histidine with tyrosine at codon 41 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown the variant to cause loss of protein function in a haploid cell proliferation assay (PMID: 30209399), reduced E3 ligase activity (PMID: 25823446) and disrupted binding to E2 ubiquitin conjugating enzyme (PMID: 16403807). This variant has been reported in at least three individuals affected with breast cancer that are described as high-risk or have a family history of breast and ovarian cancer (PMID: 28486781, 32733560, 33067490). Other missense variants at this codon have been reported as (likely) disease-causing in ClinVar (variation ID: 54166, 868161, 230862, 409353), suggesting that the conserved histidine is functionally important. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	.;T;.;.;.;D;.;T;T;.;T;D;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;T;D;D;T
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	H;H;H;H;H;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.5	N;N;N;N;N;D;N;.;N;N;N;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.039	D;D;D;D;D;.;D;.;D;.;D;.;.
Polyphen		1.0, 1.0	.;D;.;.;D;.;D;.;.;.;.;.;.
Vest4		0.85
MutPred		0.95		Loss of disorder (P = 0.1517);Loss of disorder (P = 0.1517);Loss of disorder (P = 0.1517);Loss of disorder (P = 0.1517);Loss of disorder (P = 0.1517);Loss of disorder (P = 0.1517);Loss of disorder (P = 0.1517);Loss of disorder (P = 0.1517);Loss of disorder (P = 0.1517);Loss of disorder (P = 0.1517);Loss of disorder (P = 0.1517);Loss of disorder (P = 0.1517);Loss of disorder (P = 0.1517);
MVP		0.99
MPC		0.46
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.93

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

Other links and lift over

dbSNP: rs1060502353; hg19: chr17-41267756;