17-43115738-T-C

Position:

• chr17-43115738-T-C

Variant summary

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

The ENST00000357654.9(BRCA1):​c.122A>G​(p.His41Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H41N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 ENST00000357654.9 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9 U:1 O:1
• Conservation: PhyloP100: 3.52

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 hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 17 uncertain in ENST00000357654.9
• 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-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 230862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 17-43115738-T-C is Pathogenic according to our data. Variant chr17-43115738-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 54166.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43115738-T-C is described in Lovd as [Pathogenic]. Variant chr17-43115738-T-C is described in Lovd as [Pathogenic]. Variant chr17-43115738-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.122A>G	p.His41Arg	missense_variant	3/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.122A>G	p.His41Arg	missense_variant	3/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.995 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 14, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Dec 12, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 22, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2016	This pathogenic variant is denoted BRCA1 c.122A>G at the cDNA level, p.His41Arg (H41R) at the protein level, and results in the change of a Histidine to an Arginine (CAC>CGC). Using alternate nomenclature, this pathogenic variant would be defined as BRCA1 241A>G. This variant has been observed in at least one individual with breast cancer (Kawahara 2004). BRCA1 His41Arg has been associated with weakened BARD1 binding, centrosome amplification, and inhibition of ubiquitin ligase, single strand annealing (SSA), and homology directed recombination (HDR) activities (Morris 2006, Ransburgh 2010, Kais 2012, Towler 2013). Additionally, this variant was predicted to be pathogenic by a multifactorial model based on tumor pathology, segregation, and in silico analyses (Whiley 2014). BRCA1 His41Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. BRCA1 His41Arg occurs at a position that is conserved in mammals and at an important zinc-ligating residue located within the RING domain and the binding domains of BARD1 and BRD7 (Narod 2004, Borg 2010, Harte 2010, Paul 2014). In silico analyses predict that this pathogenic variant is probably damaging to protein structure and function. The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel classifies this variant as pathogenic (ClinVar). Based on currently available evidence, we consider this variant to be pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 26, 2024	Variant summary: BRCA1 c.122A>G (p.His41Arg) results in a non-conservative amino acid change located in the Zinc finger, RING-type (IPR001841) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250784 control chromosomes. c.122A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Whiley_2014, Kawahara_2004, Tung_2015). These data indicate that the variant is likely to be associated with disease. Functional studies reported that this variant showed abrogated function in the homology directed repair assay, abrogated ubiquitin ligase and weak BARD1 binding activity (Morris_2006, Towler_2013, Ransburgh_2010). The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 23161852, 15168169, 24489791, 16403807, 20103620, 25186627). ClinVar contains an entry for this variant (Variation ID: 54166). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 30, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 16403807, 20103620, 21725363, 22843421, 23161852, 25823446, 30209399). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 54166). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 15168169, 24489791). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 41 of the BRCA1 protein (p.His41Arg). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2022

The p.H41R pathogenic mutation (also known as c.122A>G), located in coding exon 2 of the BRCA1 gene, results from an A to G substitution at nucleotide position 122. The histidine at codon 41 is replaced by arginine, an amino acid with highly similar properties. This histidine is crucial in coordinating the Zinc atom, which controls the structure of the functionally important RING domain (Brzovic PS et al. Nat. Struct. Biol. 2001 Oct; 8(10):833-7; Brzovic PS et al. Proc. Natl. Acad. Sci. U.S.A. 2003 May; 100(10):5646-51). Several independent functional assays demonstrate that although this alteration may not disrupt binding of BRCA1 to BARD1, it significantly impacts its ubiquitin ligase activity, homology directed recombination activity, single strand annealing abilities and significantly increased centrosome amplification (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). In support of these defects being inconsistent with normal BRCA1 function, a high throughput genome editing haploid cell survival assay also found this alteration deleterious (Findlay GM et al. Nature, 2018 10;562:217-222). In a study that used multifactorial likelihood analysis to assess the pathogenicity of BRCA1/2 variants, this variant was considered pathogenic with a posterior probability of pathogenicity of 0.995, largely attributable to a strong co-segregation likelihood ratio (Whiley PJ et al. PLoS ONE 2014; 9(1):e86836; Park KS et al. Genet. Med., 2016 12;18:1250-1257). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;T;.;.;.;D;.;T;T;.;T;D;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;T;D;D;T
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;H;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;N;N;N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.3	N;N;N;N;N;D;N;.;N;N;N;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.053	T;D;D;D;D;.;D;.;D;.;D;.;.
Polyphen		0.96, 1.0	.;D;.;.;D;.;D;.;.;.;.;.;.
Vest4		0.87
MutPred		0.97		Gain of MoRF binding (P = 0.0172);Gain of MoRF binding (P = 0.0172);Gain of MoRF binding (P = 0.0172);Gain of MoRF binding (P = 0.0172);Gain of MoRF binding (P = 0.0172);Gain of MoRF binding (P = 0.0172);Gain of MoRF binding (P = 0.0172);Gain of MoRF binding (P = 0.0172);Gain of MoRF binding (P = 0.0172);Gain of MoRF binding (P = 0.0172);Gain of MoRF binding (P = 0.0172);Gain of MoRF binding (P = 0.0172);Gain of MoRF binding (P = 0.0172);
MVP		1.0
MPC		0.48
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.94

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: rs80357276; hg19: chr17-41267755;