17-43045712-T-C

Variant names:

• chr17-43045712-T-C
• rs80357258
• NM_007294.4:c.5558A>G

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.5558A>G​(p.Tyr1853Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,650 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. Y1853D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • 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:8 U:1
• Conservation: PhyloP100: 4.25
• Publications: 26 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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 21 benign, 67 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 chr17-43045713-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 433738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant 17-43045712-T-C is Pathogenic according to our data. Variant chr17-43045712-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 55627.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.5558A>G	p.Tyr1853Cys	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.5558A>G	p.Tyr1853Cys	missense_variant	Exon 23 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461650 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727114

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111874

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:3

May 03, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The BRCA1 variant designated as p.Y1853C (NM_007294.3:c.5558A>G, historically referred to as 5677A>G) was previously classified as a variant of uncertain significance and is now classified as likely pathogenic. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303). Analysis of this family shows yields a likelihood ratio of 1.9 to 1 (Thompson, et al., 2003, PMID:290079) that this allele is causing cancer within the family. This BRCA1 amino acid position is highly conserved. The variant is not listed in population databases such as ExAC or gnomAD. Functional data suggests that this variant compromises the BRCT domain (Lee 2010, PMID:20516115). More recent functional data is consistent with earlier findings and also indicates that the variant leads to a non-functional protein (Findlay et al, 2018, PMID:30209399). The combined results are consistent with a classification of likely pathogenic. This variant is predicted to alter BRCA1 function and increase breast and ovarian cancer risk. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

Dec 09, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt BRCA1 protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 14534301, 20378548, 20516115, 23842040, 30209399). ClinVar contains an entry for this variant (Variation ID: 55627). This missense change has been observed in individual(s) with hereditary breast and/or ovarian cancer and breast cancer (PMID: 23842040, 29176636, 29470806, 30287823, 30374176). 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 tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1853 of the BRCA1 protein (p.Tyr1853Cys).

May 31, 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.5558A>G (p.Tyr1853Cys) 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 250374 control chromosomes. c.5558A>G has been reported in the literature from Japan, India and Brazil in individuals affected with Hereditary Breast and Ovarian Cancer (examples, Sugano_2008, Nakamura_2015, Kawaku_2013, Arai_2018, Singh_2018, Cotrim_2019, Tsai_2019). These data indicate that the variant is likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (examples, Lee_2010, Kawaku_2013, Woods_2016, Findlay_2018). The most pronounced variant effect results in a reduction of activity across multiple independent measures ranging from transcriptional assays (<10% of WT), structural stability (32% of WT), phosphopeptide binding activity (14% of WT), and protease sensitivity (30% of WT) and loss of homology directed repair (HDR) activity (Findlay_2018). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the overall directionality of evidence spanning over a decade supporting a pathogenic outcome as evidence outlined above, the variant was classified as pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:2

Nov 16, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces tyrosine with cysteine at codon 1853 of the BRCA1 protein. Computational prediction tool 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 reported that this variant impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399) and in transcription activation, phosphopeptide binding and protein stability (PMID: 20516115, 23842040). This variant has been reported in at least six individuals affected with breast and/or ovarian cancer (PMID: 19016756, 23842040, 24249303, 30606148, 30287823; Color internal data). This variant has been reported to segregate with breast cancer in at least one family (PMID: 23842040), and a multifactorial analysis has reported segregation and family history likelihood ratios for pathogenicity of 12.663 and 2.2927, respectively (PMID: 31131967). 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 Pathogenic.

Jun 23, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y1853C pathogenic mutation (also known as c.5558A>G), located in coding exon 22 of the BRCA1 gene, results from an A to G substitution at nucleotide position 5558. The tyrosine at codon 1853 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in patients with personal and/or family histories of breast and/or ovarian cancer, including many of Japanese and Indian descent (Sugano K et al. Cancer Sci. 2008 Oct;99:1967-76; Kawaku S et al. J. Hum. Genet. 2013 Sep;58:618-21; Nakamura S et al. Breast Cancer. 2015 Sep;22:462-8; Kobayashi Y et al. Jpn J Clin Oncol, 2021 Feb;51:213-217; Tokunaga H et al. PLoS One, 2021 Jan;16:e0236907; Cotrim DP et al. BMC Cancer, 2019 Jan;19:4; Arai M et al. J Hum Genet, 2018 Apr;63:447-457; Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196; Yamaguchi-Kabata Y et al. J Hum Genet, 2018 Feb;63:213-230). This alteration segregates with disease in multiple families (Kawaku S et al. J Hum Genet, 2013 Sep;58:618-21; Parsons MT et al. Hum Mutat, 2019 09;40:1557-1578). This alteration is non-functional in multiple different assays including a haploid cell survival assay, multiple protease/protein stabilization assays, peptide binding and specificity assays and transcription activation assays (Williams RS et al. J. Biol. Chem. 2003 Dec;278:53007-16; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Rowling PJ et al. J. Biol. Chem. 2010 Jun;285:20080-7; 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

Jun 20, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

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:1

Apr 15, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 19016756, 23842040, 24249303, 29176636, 30287823, 29470806, 30606148, 30374176, 35557031); Published functional studies demonstrate a damaging effect: impaired protein stability, binding, sensitivity, transciptional activity, and cell survival (PMID: 15133503, 20516115, 20378548, 23842040, 28781887, 30209399, 30765603); 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 5677G>A; This variant is associated with the following publications: (PMID: 34413315, 15235020, 23842040, 30765603, 20516115, 28781887, 31131967, 20378548, 15133503, 14534301, 30209399, 29470806, 30606148, 30374176, 30287823, 29176636, 24249303, 19016756, 17305420, 35409996, 34983974, 36010882, 35557031, 38543119, 35534113, 25348405, 35665744, 33087888)

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;T;.;T;T;T;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.0	.;M;.;.;.;.;.;.
PhyloP100		4.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-7.0	D;N;.;.;.;.;N;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;D;.;.;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Vest4		0.87
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.70
gMVP		0.75
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: rs80357258; hg19: chr17-41197729;