17-43045773-C-T

Variant names:

• chr17-43045773-C-T
• rs80357268
• NM_007294.4:c.5497G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5497G>A​(p.Val1833Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,892 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1833L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 U:2
• Conservation: PhyloP100: 4.19
• Publications: 32 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 14 benign, 75 uncertain 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 chr17-43045773-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2565337.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886
• PP5: Variant 17-43045773-C-T is Pathogenic according to our data. Variant chr17-43045773-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 55598.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.5497G>A	p.Val1833Met	missense_variant	Exon 23 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5497G>A	p.Val1833Met	missense_variant	Exon 23 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251228 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.00000506 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:4

Nov 20, 2024

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

According to the ClinGen ENIGMA BRCA1 v1.1.0 criteria we chose these criteria: PS3 (strong pathogenic): Table 9: Findlay 2018 (PMID:30209399) - LOF Petitalot 2019 (PMID:30257991) - 2P (VUS?) Bouwman 2020 (PMID:32546644) - Deleterious Fernandes 2019 (PMID:30765603) - Pathogenic, PS4 (strong pathogenic): PMID: 31447071 Greek founder mutation identified in 27/3531 HBOC patients but not in 1558 controls from greece. (OR 12 and lower 95%CI boundary 1.63) , PM2 (supporting pathogenic): not in gnomAD V3, only 1X in gnomAD V4 -

Nov 16, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA1 c.5497G>A (p.Val1833Met) results in a conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several in silico studies also predict a deleterious outcome for the variant (Carvalho_2009, Karchin_2007, Pavlicek_2004, Zhang_1998). Functional studies are in agreement with these predictions demonstrating that although the variant confers normal binding activity, it results in considerably reduced transcriptional activity and destabilizes the protein (Carvalho_2009, Fernandes_2019, Lee_2010, Rowling_2010, Woods_2016). At least one functional study reports experimental evidence evaluating an impact on protein function a damaging effect of this variant on homology directed repair (HDR) activity (e.g. Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. The variant allele was found at a frequency of 4e-06 in 251228 control chromosomes (gnomAD). c.5497G>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer, including at least one family with evidence of co-segregation with disease (Fostira_2019, Judkins_2005, Kotoula_2017, Pal_2005, Stavropoulou_2013). These data indicate that the variant is very likely to be associated with disease. Eight ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 01, 2020

GeneKor MSA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces Valine with Methionine at codon 1833 of the BRCA1 protein. The Valine residue is highly conserved among species and it is located within the BRCT domain that is important for BRCA1 function. There is a small physiochemical difference between Valine and Methionine (Grantham Score 21). This variant is also known as 5616G>A and it has been reported in the literature in individuals and families with breast and/or ovarian cancer, with some evidence of segregation with disease in a single family (PMID: 23536787, 12142080). To our Knowledge, this variant is not present in population databases (rs80357268). The mutation database ClinVar contains entries for this variant (Variation ID: 55598). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant may be damaging to the protein. These predictions have been also confirmed by published functional studies. Experimental studies have shown that this missense change affects protein folding and stability, as well as functional activity of the BRCA1 protein (PMID: 18992264, 20378548). -

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1833 of the BRCA1 protein (p.Val1833Met). This variant is present in population databases (rs80357268, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10923033, 12142080, 16284991, 23536787; internal data). It has also been observed to segregate with disease in related individuals. This variant is also known as 5616G>A. ClinVar contains an entry for this variant (Variation ID: 55598). 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: 15004537, 17493881, 18992264, 20378548, 20516115, 20526115, 28781887, 30209399). For these reasons, this variant has been classified as Pathogenic. -

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

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 20, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 02, 2020

BRCAlab, Lund University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:2 Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 06, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted BRCA1 c.5497G>A at the cDNA level, p.Val1833Met (V1833M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant, also published as BRCA1 5616G>A using alternate nomenclature, has been reported in association with breast and ovarian cancer (Ladopoulou 2002, Pal 2005, Stavropoulou 2013). While BRCA1 Val1833Met has been associated with binding activity similar to wild type, functional assays also report it significantly reduces, but does not destroy, transactivation activity in both yeast and human embryonic cell models, mildly to severely impacts protein thermostability, and abrogates the small colony phenotype in yeast (Coyne 2004, Nikolopoulos 2007, Carvalho 2009, Lee 2010, Rowling 2010). BRCA1 Val1833Met 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 Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Val1833Met occurs at a position that is conserved in mammals and is located within the BRCT2 domain and a region known to interact with multiple proteins (Paul 2014, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider BRCA1 Val1833Met to be a likely pathogenic variant. -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

May 17, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V1833M variant (also known as c.5497G>A), located in coding exon 22 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5497. The valine at codon 1833 is replaced by methionine, an amino acid with highly similar properties. This alteration has been found with enriched frequency in cohorts of Greek breast and/or ovarian cancer patients and segregated with disease in one kindred with familial ovarian cancer (Stavropoulou AV, PLoS ONE 2013; 8(3):e58182; Apessos A et al. Cancer Genet 2018 01;220:1-12; Papamentzelopoulou M et al. Cancer Genet. 2019 Sep;237:90-96). The work by Rowling et al., both experimentally and computationally showed the destabilization of the BRCT2 domain by this variant, significantly leading to unfolding and loss of function (Rowling PJ, J. Biol. Chem. 2010 Jun; 285(26):20080-7). Functional assays demonstrate reduced transactivation activity compared to wild-type (Carvalho M, Mutat. Res. 2009 Jan; 660(1-2):1-11, Woods et al, npj Genomic Medicine 1, Article number: 16001 (2016) doi:10.1038/npjgenmed.2016.1; Findlay GM et al. Nature 2018 10;562(7726):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. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Jun 04, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with methionine at codon 1833 of the BRCA1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant impairs BRCA1 function in protein folding, stability and transcriptional activation, cisplatin and PARP inhibitor sensitivity, homology-directed repair assays and in a haploid cell proliferation assay (PMID: 15004537, 17493881, 18992264, 20378548, 20526115, 28781887, 30209399, 32546644). This variant is known to be a founder mutation in the Greek population (PMID: 31447071) and has been observed in more than a dozen individuals each affected with breast or ovarian cancer (PMID: 16284991, 23536787, 31447071). One segregation analysis on multiple carrier families reported a likelihood ratio for pathogenicity of 1.88 (PMID: 31447071). However, a later multifactorial analysis reported likelihood ratios for pathogenicity based on co-segregation, tumor pathology and family history of 7.85814, 80.4827, 2.76, respectively (PMID: 35039532). This variant has also been identified in 1/251228 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Familial cancer of breast Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	.;T;.;T;T;T;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.3	.;M;.;.;.;.;.;.
PhyloP100		4.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.4	N;N;N;.;.;.;N;N
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D;D;D;.;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;.;D;.;.
Vest4		0.90
MVP		0.99
MPC		0.43
ClinPred		0.96	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.68
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80357268; hg19: chr17-41197790;