17-43067629-T-C

Variant names:

• chr17-43067629-T-C
• rs80356890
• NM_007294.4:c.5053A>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.5053A>G​(p.Thr1685Ala) 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1685S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9 U:1
• Conservation: PhyloP100: 4.79
• Publications: 35 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 22 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 78 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 chr17-43067628-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 55365.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868
• PP5: Variant 17-43067629-T-C is Pathogenic according to our data. Variant chr17-43067629-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 55364.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5053A>G	p.Thr1685Ala	missense_variant	Exon 16 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5053A>G	p.Thr1685Ala	missense_variant	Exon 16 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:4 Uncertain:1

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 10, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 10, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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 = 1 -

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.5053A>G (p.Thr1685Ala) variant in the BRCA1 gene has been reported previously in a heterozygous state in many individuals affected with breast and ovarian cancer. Experimental studies have shown that this missense change affects BRCA1 function (Findlay et al., 2018; Thouvenot et al., 2016; Lee et al., 2010). Different amino acid change affecting codon 1685 (p.Thr1685Ile) is reported as a known pathogenic variant. The amino acid Threonine at position 1685 is changed to a Alanine changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Uncertain significance/ Pathogenic. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Thr1685Ala in BRCA1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

May 16, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces a conserved threonine with alanine at codon 1685 in the BRCT domain of the BRCA1 protein (PMID: 15172985, 17305420). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Multiple functional studies have reported the mutant protein to be non-functional in a phosphopeptide binding assay, a homology-directed DNA repair assay, and cell growth/survival assay (PMID: 20516115, 27272900, 30209399, 30257991). This variant has been reported in an individual affected with breast or ovarian cancer (PMID: 24772314) and at least two suspected hereditary breast and ovarian cancer families (PMID: 11802209, 29446198). A multifactorial analysis has reported a likelihood ratio for pathogenicity based of family history of 2.0 (PMID: 17924331). This variant also has been detected in two additional individuals affected with breast cancer who also have a pathogenic BRCA2 covariant (PMID: 34296289). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at this codon, p.Thr1685Ile, is reported as disease-causing in ClinVar (variation ID: 55365) and has been reported in individuals affected with ovarian cancer (PMID: 26689913, 29297111). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Nov 12, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T1685A pathogenic mutation (also known as c.5053A>G), located in coding exon 15 of the BRCA1 gene, results from an A to G substitution at nucleotide position 5053. The threonine at codon 1685 is replaced by alanine, an amino acid with similar properties. This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Multiple functional studies have found this variant to be non-functional including a phosphopeptide binding assay; a binding specificity assay; a protease sensitivity assay; a homology-directed DNA repair assay, and a haploid cell survival assay (Lee MS et al. Cancer Res. 2010 Jun;70(12):4880-90; Petitalot A et al. Mol Cancer Res, 2019 01;17:54-69; Findlay GM et al. Nature, 2018 10;562:217-222). 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Apr 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1685 of the BRCA1 protein (p.Thr1685Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 10923033, 11802209). ClinVar contains an entry for this variant (Variation ID: 55364). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 27272900). This variant disrupts the p.Thr1685 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15172985, 15689452, 17924331, 20516115). 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. -

Sep 09, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA1 c.5053A>G (p.Thr1685Ala) results in a non-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. The variant was absent in 251378 control chromosomes. c.5053A>G has been reported in the literature in several individuals affected with clinical features of Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018, Pramanik_2024). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. 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: 30209399, 38439815, 29446198). ClinVar contains an entry for this variant (Variation ID: 55364). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1

Jun 14, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with respect to: stability, binding activity and specificity, transcription activity, and protease sensitivity (Lee 2010, Thouvenot 2016, Woods 2016, Findlay 2018, Fernandes 2019); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor 2012); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Meindl 2002, Rebbeck 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5172A>G; Not observed at significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 17305420, 17924331, 15235020, 29446198, 11802209, 24772314, 9974970, 11301010, 10220405, 24389207, 9738006, 9159119, 9926942, 10196224, 9811458, 30765603, 30209399, 20516115, 27272900, 28781887, 21990134, 27535533, 31131967, 15172985, 33087888) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;T;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	3.3	.;M;.;.;.;.;.;.;.;.
PhyloP100		4.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.0	D;N;N;D;.;N;D;D;N;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D;D;.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;.;.;D
Polyphen		0.53, 1.0	.;P;.;.;.;.;.;.;D;.
Vest4		0.89
MVP		0.95
MPC		0.083
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.96
gMVP		0.87
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs80356890; hg19: chr17-41219646;