rs80358337

Variant names:

• chr17-43092110-GACT-G
• rs80358337
• NM_007294.4:c.3418_3420delAGT

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM4_Supporting BP6

The NM_007294.4(BRCA1):​c.3418_3420delAGT​(p.Ser1140del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,928 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: BRCA1 NM_007294.4 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:7
• Conservation: PhyloP100: 0.305

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 0 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_007294.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 17-43092110-GACT-G is Benign according to our data. Variant chr17-43092110-GACT-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54876.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=3}. Variant chr17-43092110-GACT-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.3418_3420delAGT	p.Ser1140del	conservative_inframe_deletion	Exon 10 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.3418_3420delAGT	p.Ser1140del	conservative_inframe_deletion	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251122 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461606 Hom.: 0 AF XY: 0.0000110 AC XY: 8 AN XY: 727116

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: 0.0000153

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74480

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3 Benign:1

Jun 14, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 01, 2023

Department of Medical and Surgical Sciences, University of Bologna

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

BS3(Strong)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Jul 29, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jul 25, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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 specified Benign:3

Jan 25, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 10, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IF VUS: This test has identified one copy of the c.3418_3420del (p.Ser1140del) variant in the BRCA1 gene. In the published literature, this variant has been reported in individuals/families affected with melanoma (PMID: 29036293 (2017)) and hereditary breast and/or ovarian cancer (PMID: 16267036 (2005)). This variant was also reported in an individual with a pathogenic BRCA1 truncating variant in trans (PMID: 16267036 (2005)), suggesting that this variant may not cause disease. In addition, functional studies indicate that this variant complements Brca1-deficient mouse embryonic stem cells in homologous recombination DNA repair (HRR), using cisplatin and olaparib sensitivity assays as well as a direct repeat GFP (DR-GFP) assay (PMID: 32546644 (2020)). The frequency of this variant in the general population, 0.000046 (6/129040 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -

May 30, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA1 c.3418_3420delAGT (p.Ser1140del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 1.4e-05 in 1613928 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (1.4e-05 vs 0.001), allowing no conclusion about variant significance. c.3418_3420delAGT has been reported in the literature as a VUS in individual(s) affected with- or at risk for Hereditary Breast and Ovarian Cancer (Judkins 2005). Furthermore, it has been reported in a family affected with cutaneous malignant melanoma, where it was determined not to co-segregate with the disease (Goldstein 2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant(s) has been reported in the BIC database (BRCA1 c.5263_5264insC, p.Ser1755?fs), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (Bouwman_2020). These results showed no damaging effect of this variant on Homologous recombination DNA repair (HRR) by their ability to complement Brca1-deficient mouse embryonic stem cells in HRR, using cisplatin and olaparib sensitivity assays and a direct repeat GFP (DR-GFP) HRR assay. HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. This working group has recommended strong functional evidence (ACMG BS3) as sufficient weightage for categorization as likely benign (Tavtigian_2018). The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 19941162, 29036293, 32546644). ClinVar contains an entry for this variant (Variation ID: 54876). Based on the evidence outlined above, the variant was classified as likely benign. -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA1 p.Ser1140del variant was not identified in the GeneInsight-COGR, Cosmic, MutDB, ARUP Laboratories, Zhejiang Colon Cancer Database, databases. The variant was identified in dbSNP (ID: rs80358337) as “With Uncertain significance allele”; in ClinVar as likely benign by Invitae, Ambry Genetics and GeneDx, and with uncertain Significance by Counsyl and Breast Cancer Information Core. The variant was further identified in LOVD 3.0 4X with unknown significance, in UMD-LSDB database 3X as UV with no co-occurrence, in BIC Database 3X with unknown clinical significance with pending clinical classification. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Ser1140del variant has been found to reside in trans with known deleterious mutations. Functional studies of transgenic mice support the hypothesis that biallelic BRCA1 result in embryonic lethality. Therefore, it may be concluded that variants of unknown significance residing in trans with known deleterious mutations impart reduced risk for cancer (Judkins 2005). This variant is an in-frame deletion resulting in the removal of a serine residue at codon 1140; the impact of this alteration on BRCA1 protein function is not known. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Breast cancer type 1 susceptibility protein BRCA1 functional domain increasing the likelihood that it may have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hereditary breast ovarian cancer syndrome Benign:1

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs80358337; hg19: chr17-41244127;