chr17-43045759-C-G

Variant names:

• chr17-43045759-C-G
• rs80356914
• NM_007294.4:c.5511G>C

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.5511G>C​(p.Trp1837Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,880 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W1837R) 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 criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 4.19

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 helix (size 9) in uniprot entity BRCA1_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) 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 chr17-43045761-A-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 17-43045759-C-G is Pathogenic according to our data. Variant chr17-43045759-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 421244.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.5511G>C	p.Trp1837Cys	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.5511G>C	p.Trp1837Cys	missense_variant	Exon 23 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:3

May 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp1837 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8968102, 11802209, 15689452, 27741520, 28324225). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 27802165, 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: 421244). This missense change has been observed in individual(s) with hereditary breast cancer and/or ovarian cancer (PMID: 29752822; Invitae). 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 tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 1837 of the BRCA1 protein (p.Trp1837Cys). -

Nov 04, 2024

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.5511G>C (p.Trp1837Cys) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) 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 251360 control chromosomes (gnomAD). c.5511G>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Li_2019, Wan_2021). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.5509T>C, p.Trp1837Arg), supporting the critical relevance of codon 1837 to BRCA1 protein function. At least one functional study reports experimental evidence evaluating an impact on protein function and showed 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 following publications have been ascertained in the context of this evaluation (PMID: 29752822, 32803532, 30209399). ClinVar contains an entry for this variant (Variation ID: 421244). Based on the evidence outlined above, the variant was classified as pathogenic. -

May 01, 2020

Breast Center, Key Laboratory of Carcinogenesis and Translational Research

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jan 05, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces tryptophan with cysteine at codon 1837 in the BRCT2 domain 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). Functional studies have shown that this variant has reduced HDR activity, (Ambry data: https://www.ambrygen.com/science/scientific-poster/197/) exhibits severe defects in protease sensitivity, phosphopeptide binding, transcriptional activation, and has been reported to be a loss of function mutation in a haploid cell proliferation assay (PMID: 20516115, 30209399). Functional studies in yeast have shown that this variant exhibits subcellular mislocalization to the cytoplasm, reduced protein stability and a reduced ability to inhibit cell growth (PMID: 27802165). This variant has been reported in individuals affected with ovarian cancer (PMID: 31124283) and breast cancer (Lertwilaiwittaya et al. 2020, https://doi.org/10.21203/rs.3.rs-122156/v1; Color internal data). This variant has also been observed in an individual affected with breast and ovarian cancer, with early-onset breast cancer and ovarian cancer in her two sisters (PMID: 32803532). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Multiple different missense variants occurring at the same amino acid position, p.Trp1837Ser/Cys/Arg/Gly, are reported to be disease-causing, indicating that tryptophan at this position is important for BRCA1 function (ClinVar variation ID: 1065962, 421244, 37680, 853483, 55607). Based on the available evidence, this variant is classified as Pathogenic. -

Nov 29, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W1837C pathogenic mutation (also known as c.5511G>C), located in coding exon 22 of the BRCA1 gene, results from a G to C substitution at nucleotide position 5511. The tryptophan at codon 1837 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been identified in multiple breast cancer patients (Li JY et al. Int J Cancer. 2019 Jan;144:281-289; Wan Q et al. Fam Cancer. 2021 Apr;20:85-95). Multiple functional analyses have found that this nucleotide substitution to leads to a non-functional protein (Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Findlay GM et al. Nature. 2018 Oct;562:217-222; Wan Q et al. Fam Cancer. 2021 Apr;20:85-95). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:1

Feb 03, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as 5630G>C; This variant is associated with the following publications: (PMID: 26956035, 22855649, 20516115, 24845084, 30209399, 28781887, 29752822, 30765603, 31124283, 31825140) -

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

-

Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	.;T;.;T;T;T;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	.;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-11	D;N;.;.;.;.;N;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;.;.;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;.;D;.;.
Vest4		0.91
MVP		0.98
MPC		0.56
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.85

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

Other links and lift over

dbSNP: rs80356914; hg19: chr17-41197776; COSMIC: COSV104398469;