17-43092122-T-C

Position:

• chr17-43092122-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_007294.4(BRCA1):​c.3409A>G​(p.Met1137Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: -0.737

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12710026).
• BP6: Variant 17-43092122-T-C is Benign according to our data. Variant chr17-43092122-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 462610.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.3409A>G	p.Met1137Val	missense_variant	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.3409A>G	p.Met1137Val	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250962 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135732

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461476 Hom.: 0 Cov.: 39 AF XY: 0.00000275 AC XY: 2 AN XY: 727062

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 05, 2016	Variant summary: The BRCA1 c.3409A>G (p.Met1137Val) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). Met1137 is not located in any known functional domain of the Breast cancer type 1 susceptibility protein and is not highly conserved across species. This variant was found in 1/121210 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. One database classified the variant as a VUS. In the absence of clinical information and functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2023	Observed in association with a personal and/or family history of breast and/or ovarian cancer (Ryu et al., 2017; de Souza Timoteo et al., 2018; Kim et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 3528A>G; This variant is associated with the following publications: (PMID: 28364669, 30159786, 31911673, 31907386, 32467295, 30415210, 29884841, 31853058, 32377563) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 29, 2020	- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 22, 2023	The p.M1137V variant (also known as c.3409A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 3409. The methionine at codon 1137 is replaced by valine, an amino acid with highly similar properties. This alteration was classified as likely benign by a multifactorial analysis incorporating co-occurrence, personal and family history, and tumor characteristic data (Lee JS et al. J. Med. Genet., 2018 Dec;55:794-802). This alteration has been identified in 1/157 Brazilian individuals with personal and/or family history of breast cancer who were tested with a multi-gene panel (de Souza Timoteo AR et al. Breast Cancer Res. Treat., 2018 Dec;172:637-646). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 08, 2023	This missense variant replaces methionine with valine at codon 1137 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 28364669) and an individual with a personal or family history of breast cancer (PMID: 30159786). This variant also has been detected in a breast cancer case-control meta-analysis in 0/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_002540). A multifactorial analysis has reported likelihood ratios for pathogenicity, including 0.013 and 13.316 for co-occurrence with a pathogenic co-variant and tumor pathology, respectively (PMID: 30415210). This variant has been identified in 2/250962 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

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

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Mar 07, 2023

This missense variant replaces methionine with valine at codon 1137 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 28364669) and an individual with a personal or family history of breast cancer (PMID: 30159786). This variant also has been detected in a breast cancer case-control meta-analysis in 0/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_002540). A multifactorial analysis has reported likelihood ratios for pathogenicity, including 0.013 and 13.316 for co-occurrence with a pathogenic co-variant and tumor pathology, respectively (PMID: 30415210). This variant has been identified in 2/250962 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	0.25
DANN	Benign	0.32
DEOGEN2	Benign	0.41	T;.;.;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.9	L;L;.;.
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.4	N;N;N;D
REVEL	Uncertain	0.48
Sift	Benign	0.27	T;T;T;T
Sift4G	Benign	0.49	T;T;T;T
Polyphen		0.019	B;.;.;B
Vest4		0.35
MutPred		0.37		Loss of phosphorylation at S1140 (P = 0.1736);Loss of phosphorylation at S1140 (P = 0.1736);.;Loss of phosphorylation at S1140 (P = 0.1736);
MVP		0.42
MPC		0.094
ClinPred		0.051	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.066
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs771479616; hg19: chr17-41244139;