17-43124044-A-G

Variant names:

• chr17-43124044-A-G
• rs80356929
• NM_007294.4:c.53T>C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):​c.53T>C​(p.Met18Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,388 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 (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:18 U:1 O:1
• Conservation: PhyloP100: 4.17

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 14 ACMG points.

• PM1: In a helix (size 13) in uniprot entity BRCA1_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_007294.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 17-43124044-A-G is Pathogenic according to our data. Variant chr17-43124044-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 37664.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43124044-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.53T>C	p.Met18Thr	missense_variant	Exon 2 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.53T>C	p.Met18Thr	missense_variant	Exon 2 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461388 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727020

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5 Uncertain:1 Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Mar 24, 1999	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Apr 01, 2011	- -
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)	Jun 18, 2019	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 = 0.99829 -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 23, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 20, 2022	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2018	This variant is denoted BRCA1 c.53T>C at the cDNA level, p.Met18Thr (M18T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). Using alternate nomenclature, this variant would be defined as BRCA1 172T>C. BRCA1 Met18Thr has been observed in multiple individuals with breast or ovarian cancer, including male breast cancer (Langston 1996, Greenman1998, Malone 1998, van Orsouw 1999), and was reported to segregate with disease in two kindreds (Mohammadi 2009). This variant was predicted by Lindor et al. (2012) to likely be pathogenic based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious variants. Functional studies have found discordant results with respect to ubiquitin ligase activity and BARD1 binding, but have revealed impaired homology-directed repair activity, increased centrosome amplification, and loss of ability to rescue cell growth (Ruffner 2001, Morris 2004, Morris 2006, Sarkar 2008, Ransburgh 2010, Parvin 2011, Kais 2012, Bouwman 2013, Towler 2013, Starita 2015). BRCA1 Met18Thr was not observed in large population cohorts (Lek 2016). This variant is located in the RING domain and a region that binds BRD7 and BARD1 (Narod 2004, Borg 2010, Harte 2010, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available information, we consider BRCA1 Met18Thr to be a likely pathogenic variant. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 20, 2023	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 8531967 (1996), 9544766 (1998), 9523200 (1998), 19563646 (2009), 25893891 (2015), 33471991 (2021)) and ovarian cancer (PMID: 10528853 (1999), 30078507 (2018)). Published functional studies have shown that this variant results in a deleterious effect on BRCA1 protein function (PMID: 11320250 (2001), 23161852 (2013), 23867111 (2013), 25823446 (2015), 30209399 (2018)). Based on the available information, this variant is classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 16, 2024	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 18 of the BRCA1 protein (p.Met18Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 8531967, 9523200, 9544766, 10528853, 16683254, 28888541, 31907386). This variant is also known as c.172T>C. ClinVar contains an entry for this variant (Variation ID: 37664). 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: 20103620, 21725363, 23161852, 23867111, 25823446, 27272900). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Feb 14, 2019	Data included in classification: The variant was observed in 7 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing was 25,773. Case control comparison against ethnically matched population data (7/25,773 in familial cases against 0/56,696 GNOMAD NFE controls pexact= 0.00029 (PS4_VS). The variant is absent in the remainder of the GNOMAD populations (68,846 individuals) (PM2_mod). Non-functional in SGE haploid BRCA1-assay (Findlay et al. 2018) (PS3_strong). Classified as Likely Pathogenic by Ambry 2018, Gene Dx 2014, Counsyl 2018 Color LP 2018 (PP5_sup). Data not included in classification: Predicted deleterious on SIFT and Align GVGD. Predicted benign on Polyphen HumVar. There are additional reports of this variant in ClinVar (5), BIC (3) and BRCA1 LOVD (11), UMD(7), DMuDB(7). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 07, 2021	Variant summary: BRCA1 c.53T>C (p.Met18Thr) results in a non-conservative amino acid change located in the Zinc finger, RING-type domain 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 254472 control chromosomes (ACMG, PM2). c.53T>C has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (ACMG, PS4). These data indicate that the variant is very likely to be associated with disease. In functional analyses, multiple studies have reported deleterious effects of the variant, including centrosome amplification, defective BRCA1-mediated homologous repair, defective double-strand break repair, and defective homology-directed recombination (HDR) (Kais_2013, Parvin_2011, Ransburgh_2010, Towler_2013) (ACMG, PS3). In addition, multifactorial probability models have predicted the variant to be likely pathogenic or pathogenic (Lindor_2012, Easton_2007, Parsons_2019). Six submitters including an expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2019	The p.Met18Thr variant in BRCA1 has been reported at least 6 individuals with BRCA1-related cancers and segregated with disease in at least 2 affected relatives from 2 families (Malone 1998, Van Orsouew 1999, Mohammadi 2009). It was absent from large population studies, but has been reported in ClinVar (Variation ID: 37664). Computational prediction tools and conservation analyses are consistent with pathogenicity. In vitro functional studies are conflicting as to the effect of this variant on protein function (Ruffner 2001, Easteron 2007, Sarkar 2008, Millot 2011, Ransburgh 2010, Parvin 2011, Kais 2012, Lindor 2012, Bouwman 2013, Towler 2013, Whiley 2014, Starita 2016, Thouvenot 2016, Findlay 2018); however, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and ovarian cancer. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP3, PS3_Supporting. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 30, 2023	The p.M18T variant (also known as c.53T>C), located in coding exon 1 of the BRCA1 gene, results from a T to C substitution at nucleotide position 53. The methionine at codon 18 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in numerous early-onset breast and/or ovarian cancer patients and has been associated with a significant reduction in homologous-directed recombination activity compared with wild type BRCA1 (p<0.001) (Langston AA et al. N. Engl. J. Med. 1996; 334:137-42, Greenman J et al. Genes Chromosomes Cancer 1998; 21:244-9, Malone KE et al. JAMA 1998; 279:922-9, Ransburgh DJ et al. Cancer Res., 2010 Feb;70:988-95; Towler WI et al. Hum. Mutat. 2013; 34:439-45). This alteration also demonstrated reduced ubiquitin ligase activity and BARD1 binding activity as compared to wild type (Whiley PJ et al. PLoS ONE, 2014 Jan;9:e86836; Starita LM et al. Genetics. 2015 Jun;200(2):413-22). An additional functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 12, 2021	This missense variant replaces methionine with threonine at codon 18 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). Multiple functional studies have reported that this variant impacted BRCA1 function in homology-directed repair and cell proliferation assays (PMID: 21372787, 23867111, 24489791, 30219179, 30209399). This variant has been detected in at least seven individuals affected with breast and ovarian cancer (PMID: 8531967, 9523200, 10528853, 20103620, 25893891, 30078507; BIC accession number 3074), and it has also been reported to segregate with disease in carrier families (PMID: 19563646, 31131967) and has a family history likelihood ratio for pathogenicity of 25.4786 (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

Inherited ovarian cancer (without breast cancer) Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Mar 14, 2025

PS3,PS4_Very Strong,PM2,PP3,PP4_Strong -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	.;T;.;.;.;T;.;T;T;.;T;T;.;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	0.56	N;N;N;N;N;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.33	N;N;N;N;N;D;N;.;N;N;N;D;D;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;.;D;D;D;D;D;.
Sift4G	Uncertain	0.014	D;D;D;D;D;.;D;.;D;.;D;.;.;.
Polyphen		0.80, 0.95, 0.99	.;P;.;.;P;.;D;.;.;.;.;.;.;.
Vest4		0.91
MutPred		0.86		Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);
MVP		0.95
MPC		0.41
ClinPred		0.76	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.68

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: rs80356929; hg19: chr17-41276061;