17-43049179-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BP6

The NM_007294.4(BRCA1):c.5348T>C(p.Met1783Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000929 in 1,614,158 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1783I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:13 O:1
• Conservation: PhyloP100: 5.13

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 Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 17 uncertain in NM_007294.4
• BP6: Variant 17-43049179-A-G is Benign according to our data. Variant chr17-43049179-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37659.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Benign=3, Uncertain_significance=2, not_provided=1}. Variant chr17-43049179-A-G is described in Lovd as [Benign]. Variant chr17-43049179-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5348T>C	p.Met1783Thr	missense_variant	21/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5348T>C	p.Met1783Thr	missense_variant	21/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152196 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000119 AC: 30 AN: 251442 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135878

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000486 AC: 71 AN: 1461844 Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34 AN XY: 727220

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.000134

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: 0.00

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152314 Hom.: 0 Cov.: 31 AF XY: 0.000591 AC XY: 44 AN XY: 74478

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000280 Hom.: 0

Bravo AF: 0.000518

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000173 AC: 21

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:13 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Apr 25, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
Uncertain significance, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:2 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Pathway Genomics	Oct 30, 2014	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 05, 2009	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 06, 2016	Variant summary: BRCA1 c.5348C>T is a missense variant that changes a conserved T to C, resulting in an amino acid change from Met to Thr at codon 1783 in the C-terminal BRCT domain of BRCA1. This variant is predicted to be damaging by 5/5 in-silico tools. Functional studies indicate that the variant slightly reduces BRCA1 structural stability, has intermediate phosphopeptide-binding activity, reduced transcriptional activity, and 66% of wild type BRCA1 HDR function.This variant was found in 21/121366 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.001929 (20/10368). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. Although this variant was reported in multiple patients in the literature and databases, lack of co-segregation (McKean Cowdin_HumGen_2005) and multiple co-occurrences with pathogenic variants (UMD database) were found in some of these patients/families. In addition, multiple reputable sources classify this variant as likely benign/benign. Taken together, this variant was scored as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2022	See Variant Classification Assertion Criteria. -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Oct 07, 2013

- -

Breast neoplasm Uncertain:1

Uncertain significance, criteria provided, single submitter

research

A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center

-

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 03, 2022

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 p.Met1783Thr variant was identified in 2 of 838 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer and was not identified in 192 control chromosomes from healthy individuals (McKean-Cowdin 2005, Silva 2014). The variant was also identified in dbSNP (ID: rs55808233) as "With other allele", ClinVar (classified as benign by Invitae, Ambry Genetics, and two other submitters; as likely benign by GeneDx, Color, and two other submitters; and as uncertain significance by five submitters), LOVD 3.0 (15x), and UMD-LSDB (2x as likely neutral). In UMD, the variant was reported with a co-occurring, pathogenic BRCA1 variants c.755_761del (p.Arg252LeufsX44) and c.-200_80del (p.Met1SerfsX13), increasing the likelihood that the p.Met1783Thr variant does not have clinical significance. The variant was identified in control databases in 45 of 277188 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 41 of 24028 chromosomes (freq: 0.002, increasing the likelihood this could be a low frequency benign variant), Other in 2 of 6462 chromosomes (freq: 0.0003), and Latino in 2 of 34420 chromosomes (freq: 0.00006), while it was not observed in the European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. Although the p.Met1783 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the M variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. There are conflicting results in the literature regarding the effect of this variant on the BRCA1 protein, specifically within the BRCT domain where this variant is located. Functional studies demonstrated that the variant may be moderately destabilizing to the protein folding (Drikos 2009, Glover 2006, Williams 2003, Rowling 2010) but that protein binding capabilities of the mutant protein were similar to the wild type (Drikos 2009, Glover 2006) and that the mutant protein retains between 50-70% DNA repair activity relative to the wild type (Gaboriau 2015, Lu 2015). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.0045	T
BayesDel_noAF	Pathogenic	0.21
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.22	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.5	D;N;.;.;.;.;N;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D;D;.;.;.;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D
Polyphen		0.99, 1.0	.;D;.;.;.;D;.;.
Vest4		0.87
MVP		0.94
MPC		0.34
ClinPred		0.12	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
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: rs55808233; hg19: chr17-41201196; COSMIC: COSV99070735;